IE71943B1 - Benzimidazoles drugs containing these compounds and process for their preparation - Google Patents

Benzimidazoles drugs containing these compounds and process for their preparation

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Publication number
IE71943B1
IE71943B1 IE124690A IE124690A IE71943B1 IE 71943 B1 IE71943 B1 IE 71943B1 IE 124690 A IE124690 A IE 124690A IE 124690 A IE124690 A IE 124690A IE 71943 B1 IE71943 B1 IE 71943B1
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IE
Ireland
Prior art keywords
group
carbon atoms
methyl
butyl
alkyl
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IE124690A
Other versions
IE901246L (en
Inventor
Berthold Dr Narr
Andreas Dr Bomhard
Norbert Dr Hauel
Wolfgang Dr Wienen
Michael Dr Entzeroth
Meel Jacques Dr Van
Original Assignee
Thomae Gmbh Dr K
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Priority claimed from DE3911603A external-priority patent/DE3911603A1/en
Application filed by Thomae Gmbh Dr K filed Critical Thomae Gmbh Dr K
Publication of IE901246L publication Critical patent/IE901246L/en
Publication of IE71943B1 publication Critical patent/IE71943B1/en

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    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
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    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/12—Radicals substituted by oxygen atoms
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    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
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    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/26—Oxygen atoms
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    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/28—Sulfur atoms
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    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical
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    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Abstract

The invention relates to benzimidazoles of the formula <IMAGE> in which R1 to R6 are defined as in claim 1, their 1- and 3-isomer mixtures and their acid addition salts, which have useful properties. The novel compounds are in particular angiotensin II antagonists.

Description

Benzimidazoles, drugs containing these compounds and process for their preparation EP-A-0,132,606 describes 4(benzimidazol-l-yl)-methylbiphenyls which are insecticides and acaricides. US-A4,880,804 also describes 4'-(benzimidazol-l-yl)-methylbiphenyls which are angiotensin-II antagonists, but the compounds of the present invention which do not benefit from any rights to the priorities claimed do not fall within the scope of US-A-4,880,804, as the latter does not claim any compounds which are substituted in the phenyl nucleus of the benzimidazole group by an optionally substituted amino group.
It has been found, surprisingly, that 41 - (benzimidazol-115 yl)-methyl-biphenyls which are substituted by an acylated amino or imino group in the phenyl nucleus of the benzimidazole group are superior angiotensin-II antagonists.
The present invention therefore relates to 1 and 3 isomers of the benzimidazoles of the formula and, provided that Rx and R2 are not both a hydrogen atom at the same time or do not both have the same meanings in the 4 and 7 position or in the 5 and 6 position, the 1 and 3 isomer mixtures thereof and the addition salts thereof, in particular for the pharmaceutical use of their physiologically acceptable addition salts with inorganic or organic acids or bases.
In the above formula I Rx denotes a hydrogen, fluorine, chlorine or bromine atom, an alkyl group having 1 to 4 carbon atoms, which may be 943 substituted by a hydroxy, alkoxy, amino, alkylamino, dialkylamino or acylamino group, an alkoxy group having 1 to 4 carbon atoms, which may be substituted in the 2, 3 or 4 position by a hydroxy, alkoxy, amino, alkyl amino, dialkylamino or imidazolyl group, a hydroxy, phenylalkoxy, acyloxy, trifluoromethylsulphonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, cycloalkylaminocarbonyloxy, cycloalkylalkylaminocarbonyloxy, arylaminocarbonyloxy, aralkylaminocarbonyloxy, alkoxycarbonyloxy, cycloalkoxycarbonyloxy, cycloalkylalkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, trifluoromethyl, cyano, nitro, alkylmercapto, alkylsulphinyl, alkylsulphonyl, aminosulphonyl, alkylaminosulphonyl, dialkylaminosulphonyl, arylaminosulphonyl, acylaminosulphonyl or acyl group, an amino group, which may be monosubstituted by an imidazolylalkyl, dialkylaminoalkanoyl, acyl, cycloalkoxycarbonyl, cycloalkylalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl or trifluoroacetyl group, by a bicyclic or tricyclic alkyl group having 7 to 11 carbon atoms, by an alkylsulphonyl group having 1 to 4 carbon atoms, by an alkoxycarbonyl group having a total of 2 to 7 carbon atoms or by a thiazolidin-3-ylcarbonyl group substituted by an alkoxycarbonyl group, an alkylamino group having 1 to 6 carbon atoms, which may be substituted at the nitrogen atom by an alkyl, alkylsulphonyl or acyl group, wherein, if the acyl group is an alkanoyl group, it may be additionally substituted by an alkoxy group, and the alkyl substituent may be substituted at position 2 by a hydroxy, alkoxy or arylamino group, an amino group monosubstituted or disubstituted by a cycloalkyl, cycloalkylalkyl, phenylalkyl or phenyl group, wherein the substituents may be the same or different, an N-alkyl-cycloalkylamino, N-alkyl-cycloalkylalkylamino, N-alkyl-phenylalkylamino or N-alkyl-phenylamino group, a Pyrrolidino, piperidino or hexamethyleneimino group optionally substituted by an alkyl, cycloalkyl or phenyl group, an N-alkoxycarbonyl-alkylamino, N-cycloalkoxycarbonyl15 alkylamino, N-cycloalkylalkoxycarbonyl-alkylamino, Naryloxycarbonyl-alkylamino or N-aralkoxycarbonylalkylamino group, in which the alkyl group may contain 1 to 6 carbon atoms in each case, an alkoxycarbonylamino, cycloalkoxycarbonylamino, cycloalkylalkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, acylamino or alkylsulphonylamino group substituted at the nitrogen atom by a cycloalkyl, cycloalkylalkyl or aralkyl group, a carbonyl group, which is substituted by an alkyl group which is substituted in the 2 or 3 position by a hydroxy, alkanoyloxy or alkylamino group, by a hydroxycarbonylalkyl, hydroxy, alkoxy, amino, cycloalkylamino, cycloalkylalkylamino, arylamino or aralkylamino group, by an alkylamino group substituted 3Q in the 2 or 3 position by an arylamino group, or by an alkylamino group having 1 to 5 carbon atoms and optionally substituted by a carboxy group in the alkyl part, which may be substituted in each case additionally at the nitrogen atom by an -alkyl group, an aminoacetylamino group optionally substituted by an alkoxycarbonyl group having a total of 2 to 5 carbon atoms, an aminocarbonylamino or aroinothiocarbonylamino group, which may be monosubstituted, disubstituted or trisubstituted by an alkyl group having l to 20 carbon atoms, by an alkenyl or alkynyl group having 3 to 5 carbon atoms in each case, by a bicyclic or tricyclic alkyl group having 7 to 11 carbon atoms, by a cycloalkyl, cycloalkylalkyl, aralkyl or aryl group, wherein the substituents may be the same or different, and a methylene group in a cycloalkyl radical having 5 to 7 carbon atoms may be replaced by an oxygen atom, and an alkyl group may besubstituted in the 4, 5 or 6 position by a hydroxy, alkanoyl or trifluoroacetyl group, a cycloalkyleneiminocarbonylamino group having 4 to 6 carbon atoms in the cycloalkyleneimino moiety or a morpholinocarbonylamino group, which may both be substituted at the amino nitrogen by an alkyl group having 1 to 20 carbon atoms, or by a cycloalkyl, cycloalkylalkyl/ aralkyl or aryl group, a phthalimino, homophthalimino, 2-carboxypheny1carbonylamino, 2-carboxyphenylmethylamino, 2carboxyphenylmethylenecarbonylamino or 2carboxymethylenephenylcarbonylamino group, whilst a carbonyl group in a phthalimino group may be replaced by a methylene group and a methylene group in a homophthal imino, 2 -carboxypheny lmethy lenecarbony lamino or 2 -carboxymethylenephenylcarbonylamino group may be substituted by one or two alkyl groups, and additionally the above-mentioned phenyl nuclei may be mono- or disubstituted by alkyl or alkoxy groups, whilst the substituents may be identical or different, and at the same time they may be partially or wholly hydrogenated, a bicycloalkane-3-carboxylic acid amino or bicycloalkene-3-carboxylic acid amino group substituted by a carboxy group in the 2-position, a bicycloalkane5 2,3-dicarboxylic acid imino or bicycloalkene-2,3dicarboxylic acid imino group, wherein the bicycloalkane and bicycloalkene parts each contain 9 or 10 carbon atoms, may be substituted by 1, 2 or 3 methyl groups and an endomethylene group may be replaced by an oxygen atom, a glutaric acid imino or 3-carboxy-n-propylenecarbonyl group wherein the n-propylene group may be perfluorinated, substituted by one or two alkyl groups or by a tetramethylene or pentamethylene group, or a 5,7-dioxa-lH,3H-imidazo[l,5-c]thiazolyl group, R2 denotes the meanings for Ri mentioned above, a 2imidazolidon-l-yl or 3,4,5,6-tetrahydro-2-pyrimidon-l-yl group optionally substituted in the 3 position by an alkyl, cycloalkyl, cycloalkylalkyl or aralkyl group, or a tetrazolyl group or Rx and Rz together with 2 carbon atoms of the 2q neighbouring phenyl ring denote a phenyl or l-alkyl-3, 3-dialky1-2,3-dihydropyrrol-2-one group, R3 denotes a hydrogen, fluorine, chlorine or bromine atom, an alkyl group having 1 to 6 carbon atoms, in which a methylene group may be replaced by an oxygen or sulphur atom, a sulphinyl, sulphonyl or alkylamino group, and a methyl group may be substituted by a hydroxy, alkoxy, amino, alkylamino or dialkylamino group, but wherein the methylene group next to the benzimidazole ring may not be replaced by a sulphinyl or sulphonyl group, and when a methylene group is replaced and a methyl group is substituted at the same time, they must be separated from one another by at least 2 carbon atoms, an alkenyl or alkynyl group each having 3 to 5 carbon atoms, a phenylalkyl group, a cycloalkyl or cycloalkylalkyl group, in which the cycloalkyl moiety may contain 5 to 7 carbon atoms in each case, an aryl, hydroxy or imidazolylalkylamino group, an alkylamino group having 1 to 4 carbon atoms, an aminocarbonyl group, which may be substituted by an alkyl or cycloalkyl group having 5 to 7 carbon atoms, a 5-membered heteroaromatic ring, which contains an NH group, an oxygen or sulphur atom, wherein this 5membered heteroaromatic ring mentioned above may additionally contain a further 1 to 3 N atoms, or a 6membered heteroaromatic ring, which may contain 1 or 2 nitrogen atoms, wherein the 5-membered and 6membered heteroaromatic rings mentioned above may be substituted by one or, with the exception of the tetrazolyl group, by two alkyl groups, R4 denotes an amino, phthalimino, aminomethyl, cyano, tert. -butoxycarbonyl or 1- (triphenylmethyl) -tetrazolyl group, agroup containing a Brfinsted acid or a radical which can be converted in vivo to a group containing a Brfinsted acid, R5 and R6 each denote a hydrogen atom or Rs and Rg together with the two ortho position carbon atoms denote a phenyl group.
The term a group containing a BrBnsted acid" mentioned above especially means in this case a carboxy, aminoacetylamino, trifluoromethylcarbonylamino, trifluoromethylcarbonylaminomethyl, trifluoromethylsulphonylamino, trifluoromethylsulphonylaminomethyl or ΙΗ-tetrazolyl group, an alkylcarbonylamino, alkylcarbonylaminomethyl, arylcarbonylamino, arylcarbonylaminomethyl, aralkylcarbonylamino, aralkylcarbonylaminomethyl, alkylsulphonylami.no, alkyl sulphonyl aminomethyl, arylsulphonylamino, arylsulphonylaminomethyl, aralkylsulphonylamino, aralkylsulphonylaminomethyl, arylsulphonylaminocarbonyl or benzylsulphonylaminocarbonyl group, an alkylsulphonylaminocarbonyl or perfluoroalkylsulphonylaminocarbonyl group having in each case 1 to 6 carbon atoms in the alkyl moiety, a radical which can be converted in vivo to a group containing a BrBnsted acid, with the exception of the tert.-butoxycarbonyl group, especially means an alkoxycarbonyl group having a total of 2 to 7 carbon atoms, such as the methoxycarbonyl, ethoxycarbonyl, npropoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, ri-pehtoxycarbonyl or n-hexoxycarbonyl group, an aralkoxycarbonyl group, such as the benzyloxycarbonyl, 1-phenylethoxycarbonyl, 2phenylethoxycarbonyl or 3-phenylpropoxycarbonyl group or the pivaloyloxymethoxycarbonyl, phthalidylmethoxycarbonyl, ethoxycarbonyloxyethoxycarbonyl, methoxymethoxycarbonyl, cyclohexyloxycarbonylmethoxycarbony1 or (1,3-dioxa-2-oxo-4-methylcyclopenten-5-yl)-methoxycarbonyl group, an acyl group especially means an alkanoyl group having 1 to 7 carbon atoms, a cycloalkylcarbonyl group having a total of 4 to 8 carbon atoms, a cycloalkylalkanoyl group having a total of 5 to 10 carbonatoms, or an arylcarbonyl, aralkanoyl or phenylsulphonyl group optionally substituted by a fluorine, chlorine or bromine atom or by an alkyl or alkoxy group, an aryl group especially means a phenyl group optionally substituted by a fluorine, chlorine or bromine atom, or by a hydroxy, alkyl, alkoxy, phenylalkoxy or trifluoromethyl group, wherein the alkyl moiety may contain 1 to 4 carbon atoms in each case, or a naphthyl group, and a cycloalkyl group especially means a cycloalkyl group having 3 to 7 carbon atoms, which may be substituted by one or two alkyl groups, wherein, provided that nothing else has been mentioned, the alkyl and alkanoyl moieties mentioned in the definition of the radicals Rx to R3, and the alkyl moieties mentioned above may contain 1 to 3 carbon atoms in each case.
The novel compounds of the above formula I have valuable properties. Hence, the compounds of the formula I, in which Ra denotes a group containing a Brttnsted acid or a radical which can be converted in vivo to a group containing a Brbnsted acid, have valuable pharmacological properties, in particular these compounds are angiotensin II antagonists.
The remaining compounds of the formula I are valuable intermediates as they can be converted chemically to one of the pharmacologically active compounds of the formula I mentioned above.
The present invention thus also relates to novel medicaments which contain one of the above-mentioned pharmacologically active compounds of the formula I or a corresponding physiologically acceptable salt, and are particularly suitable for the treatment of hypertonia and cardiac insufficiency, also for the treatment of ischaemic peripheral circulatory disorders, myocardial ischaemia (Angina), for the prevention of cardiac insufficiency progression after myocardial infarction, for the treatment of diabetic nephropathy, glaucoma, gastrointestinal illnesses and diseases of the bladder.
Suitable examples of the meanings mentioned in the definition of the radicals Rlz Rz, R3 and RA are for Rx the meaning hydrogen, fluorine, chlorine or bromine atom, methyl, ethyl, n-propyl, isopropyl, nbutyl, hydroxymethyl, 2-hydroxyethyl, 2-hydroxyisopropyl, 3-hydroxypropyl, methoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-methoxyisopropyl, 2-n-propoxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, 3-aminopropyl, methylaminomethy1, dimethylaminomethyl, ethylaminomethy 1 , diethylaminomethyl, N-methyl-isopropylaminomethyl, 2-methylaminoethyl, 2-dimethylaminoethyl, 2isopropylaminoethyl, 2-diisopropylaminoethyl, 325 methylaminopropyl, 3-dimethylaminopropyl, acetaminomethyl, propionylaminomethyl, butanoylaminomethyl, pentanoylaminomethyl, benzoylaminomethyl, benzenesulphonylaminomethy1, 2-acetaminoethyl, 2propionylaminoethyl, 2-butanoylaminoethyl, 2-benzoyl30 aminoethyl, 3-acetaminopropyl, methoxy, ethoxy, npropoxy, isopropoxy, n-butoxy, 2-hydroxyethoxy, 2hydroxyisopropoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 2ethoxyethoxy, 2-methoxyisopropoxy, 3-methoxypropoxy, 3n-propoxypropoxy, 2-aminoethoxy, 2-methylaminoethoxy, 235 dimethylaminoethoxy, 2-ethylaminoethoxy, 2-diethylaminoethoxy, 2-isopropylaminoethoxy, 3-aminopropoxy, 3methylaminopropoxy, 3-dimethylaminopropoxy, 2-(imidazol10 1-yl)-ethoxy, 2-(imidazol-2-yl)-ethoxy, 2-(imidazol-4yl)-ethoxy, 3-(imidazol-l-yl)-propoxy, 3-(imidazol-2yl)-propoxy, 3-(imidazol-4-yl)-propoxy, hydroxy, benzyloxy, 2-phenylethoxy, 3-phenylpropoxy, acetoxy, propionyloxy, n-butanoyloxy, n-pentanoyloxy, trifluoromethylsulphonyloxy, methylaminocarbonyloxy, ethylaminocarbonyloxy, isopropylaminocarbonyloxy, dimethy laminocarbonyloxy, diethylaminocarbonyloxy, di-npropylaminocarbonyloxy, N-methyl-ethylaminocarbony-loxy, cyclopropylaminocarbonyloxy, cyclobutylaminocarbonyloxy, cyclopentyl aminocarbonyl oxy, cyclohexylaminocarbonyloxy, cycloheptylaminocarbonyloxy, cyclopropy lmethylaminocarbonyloxy , cyclobutylmethylaminoearbonyloxy, cyclopentylmethylaminocarbonyloxy, cyclo15 hexy lmethylaminocarbonyloxy, cyclohepty lmethylaminocarbonyloxy , (2 -cyclopropy lethyl) -aminocarbonyl oxy, (2cyclobuty lethyl)-aminocarbonyloxy, (2-cyclopentylethyl)-aminocarbonyloxy, (2-cyclohexylethyl)aminocarbonyloxy, (2-cycloheptylethyl) -aminocarbonyloxy, 2o ( 3 -cyclopropylpropyl) -aminocarbonyloxy, (3-cyclobutylpropyl) -aminocarbonyloxy, (3-cyclopentylpropyl) -aminocarbonyloxy, (3-cyclohexylpropyl)-aminocarbonyloxy, (3cycloheptylpropyl)-aminocarbonyloxy, methoxycarbonyloxy, ethoxycarbonyloxy, n-propoxycar-bonyloxy, isopropoxycarbonyloxy, cyclopropoxycarbonyl-oxy, cyclobutoxycarbonyloxy, cyclopentoxycarbonyloxy, cyclohexoxycarbonyloxy, cycloheptoxycarbonyloxy, cyclopropy lmethoxycarbonyloxy , cyclobutylmethoxycarbonyloxy, cyclopenty lmethoxycarbonyloxy, cyclohexylmethoxy30 carbonyloxy, cyclohepty lmethoxycarbonyloxy, (2cyclopropylethoxy) -carbonyloxy, (2 -cyclobutylethoxy) carbonyloxy, (2-cyclopentylethoxy)-carbonyloxy, (2cyclohexylethoxy) -carbonyloxy, (2-cycloheptyleth-oxy) carbonyloxy, (3-cyclopropy lpropoxy)-carbonyloxy, (335 cyclobuty lpropoxy.)-carbonyloxy, (3-cyclopentylpro-poxy)carbonyloxy, (3-cyclohexy lpropoxy)-carbonyloxy, (3cycloheptylpropoxy) -carbonyloxy, phenyloxycarbonyl-oxy,· benzyloxycarbonyloxy, (2-phenylethoxy)-carbonyloxy, trifluoromethyl, phenylaminocarbonyloxy, benzylaminocar bonyloxy, (2-phenylethyl)-aminocarbonyloxy, cyano, nitro, methylmercapto, ethylmercapto, n-propylmercapto, isopropylmercapto, methylsulphinyl, ethylsulphinyl, npropylsulphinyl, isopropylsulphinyl, methylsulphonyl, ethylsulphonyl, n-propylsulphonyl, isopropylsulphonyl, phenylsulphonyl, fluorophenylsulphonyl, chlorophenylsulphonyl, bromophenyl sulphonyl, methylphenylsulphonyl, ethylphenylsulphonyl, isopropylphenylsulphonyl, methoxy phenylsulphonyl, ethoxyphenylsulphonyl, n-propoxyphenyl sulphonyl, aminosulphonyl, methylaminosulphonyl, ethylaminosulphonyl, n-propylaminosulphonyl, isopropylaminosulphonyl, dimethylaminosulphonyl, diethylaminosulphonyl, di-n-propylaminosulphonyl, N-methylethylaminosulphonyl, phenylaminosulphonyl, fluorophenylaminosulphonyl, chlorophenylaminosulphonyl, bromophenylaminosulphonyl, methylphenylaminosulphonyl, ethylphenylaminosulphonyl, isopropylphenylaminosulphonyl, methoxyphenylaminosulphonyl, ethoxyphenylaminosulphony 1 , n-propoxyphenylaminosulphonyl, acetaminosulphonyl, propionylaminosulphonyl, n-butanoylaminosulphonyl, benzoyl aminosulphonyl, f luorobenzoylaminosulphonyl, chlorobenzoylaminosulphonyl, bromobenzoylaminosulphony1, methylbenzoylaminosulphony1, methoxybenzoylaminosulphonyl, acetyl, propionyl, n-butanoyl, n pentanoyl, n-hexanoyl, n-heptanoyl, phenylacetyl, 2phenylpropionyl, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbony1, cycloheptylcarbonyl, cyclopropylmethylcarbonyl, cyclobutylmethyl carbonyl, cyclopentylmethylcarbonyl, cyclohexylmethy1carbony1, cycloheptylmethylcarbony1, (2-cyclopropylethyl )-carbonyl, (2-cyclobutylethyl)-carbonyl, (2cyclopentylethyl) -carbonyl, (2-cyclohexylethyl) carbonyl, (2-cycloheptylethyl)-carbonyl, (3-cyclopropylpropy1)-carbonyl, (3-cyclobutylpropy1)-carbonyl, (3-cyclopentylpropyl) -carbonyl, (3-cyclohexylpropy 1)12 carbonyl, (3-cycloheptylpropyl)-carbonyl, benzoyl, fluorobenzoyl, chlorobenzoyl, bromobenzoyl, methylbenzoyl, methoxybenzoyl, phenylsulphonyl, fluorophenylsulphonyl, chlorophenylsulphonyl, bromophenyl5 sulphonyl, methylphenylsulphonyl, methoxyphenylsulphonyl, amino, 2-(imidazol-l-yl) -ethylamino, 2(imidazol-l-yl)-isopropylamino, 3-(imidazol-l-yl)propylamino, (imidazol-4-yl)-methylamino, 2-(imidazol-4yl)-ethylamino, 2-(imidazol-4-yl)-isopropylamino, 310 (imidazol-4-yl)-propylamino, acetylamino, propionylamino, n-butanoylamino, isobutanoylamino, npentanoylamino, n-hexanoylamino, n-heptanoylamino, cyclopropylcarbonylamino, cyclobutylcarbonylamino, cyclopentylcarbonylamino, cyclohexylcarbonylamino, cycloheptylcarbonylamino, cyclopropylmethylcarbonylamino, cyclobutylmethylcarbonylamino, cyclopentyl. methylcarbonylamino, cyclohexylmethylcarbonylamino, cycloheptylmethylcarbonylamino, (2-cyclopropylethyl)carbonylamino, (2-cyclobutylethyl)-carbonylamino, (220 cyclopentylethyX)-carbonylamino, (2-cyclohexyl-ethyl)carbonylamino, (2-cycloheptylethyl)-carbonyl-amino, (3cyclopropy lpropyl) -carbonylamino ,(3 -cyclobutylpropyl) carbonylamino, (3-cyclopentylpropyl) -carbonylamino, (3cyclohexylpropyl) -carbonylamino ,(3 -cycloheptylpropyl) 25 carbonylamino, benzoylamino, fluorobenzoylamino, chlorobenzoylamino, bromobenzoyl-amino, methylbenzoylamino, hydroxybenzoylamino, methoxybenzoylamino, phenylacetylamino, phenyl propionylamino, naphthylcarbonylamino, methoxycarbonylamino, ethoxy30 carbonylamino, n-propoxycarbonylamino, cyclopropyloxycarbonylamino, cyclobutyloxycarbony lamino, cyclopentoxycarbonylamino, cyclohexoxycarbonylamino, cycloheptoxycarbonylamino, cyclopropylmethoxycarbony lamino, cyclobutylmethoxycarbonylamino, cyclopentylmethoxycarbonyl35 amino, cyclohexylmethoxycarbonylamino, cycloheptylmethoxycarbonylamino, (2-cyclopropylethoxy)-carbonylamino , (2-cyclobutylethoxy)-carbonylamino, (213 cyclopentylethoxy)-carbonylamino, (2-cyclohexylethoxy) carbonylamino, (2-cycloheptylethoxy)-carbonylamino, (3cyclopropylpropoxy)-carbonylamino, (3-cyclobutylpropoxy)-carbonylamino, (3-cyclopentylpropoxy)-carbonyl5 amino, (3-cyclohexylpropoxy)-carbonylamino, (3-cycloheptylpropoxy) -carbonylamino, phenoxycarbonylamino, fluorophenoxycarbonylamino, chlorophenoxycarbonylamino, bromophenoxycarbonylamino, methylphenoxycarbonylamino, hydroxyphenoxycarbonylamino, methoxyphenoxycarbonylamino, benzyloxyphenoxycarbonylamino, benzyloxycarbonylamino, (2-phenylethoxy)-carbonylamino, trifluoroacetylamino, decalinylamino, adamantylamino, methy1sulphonylamino, ethylsulphonylamino, n-propylsulphonylamino, nbutylsulphonylamino, methylamino, ethylamino, npropylamino, isopropylamino, n-butylamino, isobutylamino, n-pentylamino, n-hexylamino, dimethylamino, diethylamino, di-n-propylamino, methy1-ethylamino, methyl-isopropylamino, methyl-n-butylamino, ethyl-npropylamino, N-n-propylsulphonyl-methylamino, methyl-n20 pentylamino, ethyl-n-hexylamino, N-methylsulphonylmethylamino, N-ethylsulphonyl-methylamino, N-n-propylsulphonyl-methylamino, N-methylsulphonyl-ethylamino, Nethylsulphonyl-ethylamino, N-n-propylsulphonyl-ethylamino, N-methylsulphonyl-n-propylamino, N-ethylsul-5 phonyl-n-propylamino, N-n-propylsulphonyl-n-propylamino N-methylsulphonyl-n-butylamino, N-ethylsulphonyl-npentylamino, N-n-propylsulphonyl-n-hexylamino, N-acetyl methylamino, N-acetyl-ethylamino, N-acetyl-n-hexylamino N-propionyl-methylamino, N-propionyl-ethyl-amino, N10 propionyl-n-butylamino, N-n-butanoyl-methyl-amino, N-nbutanoyl-ethylamino, N-n-butanoyl-n-pentyl-amino, Nisobutanoyl-methylamino, N-isobutanoyl-ethyl-amino, Nisobutanoyl-isopropylamino, N-isobutanoy1-n-pentylamino N-n-pentanoyl-methylamino, N-n-pentanoyl-ethylamino, N5 n-pentanoyl-isopropylamino, N-n-pentanoyl-n-pentylamino N-n-hexanoyl-methylamino, N-n-hexanoyl-ethylamino, N-nhexanoyl-isopropy lamino, N-n-hexanoyl-n-pentylamino, N14 n-heptanoyl-methylamino, N-n-heptanoyl-ethylamino, N-nheptanoyl-isopropylamino, N-n-heptanoyl-n-pentylamino, N-cyclopropyl-carbonylmethyl-amino, Ncyclobutylcarbonyl-methylamino, N-cyclopentylcarbonylraethylamino, N-cyclohexylcarbonyl-methylamino, N-cycloheptylcarbonyl-methylamino, N-cyclopropylmethylcarbonylmethylamino, N-cyclobuty lmethy lcarbonyl-methylamino, Ncyclopenty1-methylcarbonyl-methylamino, Ncyclohexylmethylcarbonyl-methylamino, Ncycloheptylmethylcarbonyl-methylamino, N-(2cyclopropylethylcarbonyl)-methylamino, N-(2cyclobutylethylcarbonyl)-methylamino, N- (2cyclopentylethylcarbonyl)-methylamino, N-(2-cyclohexylethylcarbonyl)-methylamino, N-(2-cycloheptylethylcarbony1) -methylamino, N- (3 -cyclopropylpropyl -carbonyl) methylamino, N-(3-cyclobutylpropy1-carbonyl)methylamino, N—(3-cyclopentylpropy1-carbonyl)methylamino, N- (3-cyclohexylpropy1-carbonyl )methylamino, N- (3-cycloheptylpropyl-carbonyl )methylamino, N-benzoyl-methylamino, N-benzoylethylamino, N-benzoyl-isopropylamino, N-benzoyl-nbutylamino, N-benzoyl-n-pentylamino, N-benzoyl-nhexy lamino, N-fluorobenzoyl-methyl amino, Nmethylbenzoyl-ethylamino, N-methoxybenzoylisopropylamino, N-chlorobenzoyl-n-butylamino, Nfluorobenzoy1-n-pentylamino, N-bromobenzoy 1-nhexylamino, N-phenylacetyl-methylamino, N-phenylsulphony1-methylamino, N- (2-hydroxyethyl)-methyl-amino, N-(2-hydroxyethyl)-ethyl-amino, N- (2-methoxyethyl)methylamino, N-(2-methoxy-ethyl)-ethylamino, N-hydroxyacetyl-methylamino, N-hydroxyacetyl-ethylamino, Nmethoxy acetyl-methylamino, N-methoxyacetyl-ethylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, cyclopropylmethylamino, cyclobutylmethy1-amino, cyclopentylmethylamino, cyclohexylmethylamino, cycloheptylmethylamino, (2-cyclopropylethyl)-amino, (2-cyclobutylethyl)-amino, (215 cyclopentylethyl)-amino, (2-cyclohexylethyl)-amino, (2cycloheptylethyl)-amino, (3-cyclopropylpropyl)-amino, (3-cyclopentylpropyl)-amino, (3-cyclohexylpropyl)-amino (3-cycloheptyl-propyl)-amino, benzylamino, 2phenylethyl-amino, 3-phenylpropylamino, phenylamino, dicyclohexyl-amino, dicyclohexylmethylamino, dibenzylamino, N-methyl-cyclopropylamino, N-isopropylcyclopropylamino, N-ethyl-cyclobutylamino, N-methylcyclopentylamino, N-ethyl-cyclohexylamino, N-(n-propyl) cycloheptylamino, N-methyl-cyclopropylmethylamino, Nisopropy1-cyclopropylmethylamino, N-ethy1cyclobutylmethylamino, N-methyl-cyclopentylmethylamino, N-ethyl-cyclohexyl-methylamino, N-(n-propyl)cycloheptylmethylamino, N-methyl-(2-cyclopropylethyl)amino, N-isopropyl-(2-cyclopropylethyl)-amino, N-ethyl(2-cyclobutylethyl)-amino, N-methyl-(2cyclopentylethyl)-amino, N-ethyl-(2-cyclohexylethyl)amino, N-(n-propyl)-(2-cycloheptyl-ethyl)-amino, Nmethyl-(3-cyclopropylpropyl)-amino, N-isopropyl-(3cyclopropylpropylj-amino, N-ethyl-(3-cyclobutylpropyl)amino, N-methyl-(3-cyclopentylpropyl)-amino, N-ethyl-(3 cyclohexylpropyl)-amino, N-(n-propyl)-(3cycloheptylpropyl)-amino, N-methyl-benzyl-amino, Nethyl-benzylamino, N-isopropyl-benzylamino, N-methyl-(2 phenylethyl)-amino, N-methy1-phenylamino, N-(n-propyl)phenylamino, pyrrolidino, methyl-pyrrolidino, ethylpyrrolidino, isopropylpyrroli-dino, cyclopentylpyrrolidino, cyclohexylpyrrolidino, cycloheptylpyrrolidino, phenylpyrrolidino, piperidino, methylpiperidino, ethylpiperidino, isopropylpiperidino, cyclopentylpiperidino, cyclohexylpiperidino, cycloheptylpiperidino, phenylpiperidino, hexamethyleneimino, methylhexamethyleneimino, ethylhexamethyleneimino, isopropylhexamethyleneimino, cyclopentylhexamethyleneimino, cyclohexylhexamethylene imino, cycloheptylhexamethyleneimino, phenylhexamethyleneimino, Nmethoxycarbonyl-methylamino, N-methoxycarbonyl-N16 ethylamino, N-methoxycarbonyl-n-pentylamino, Nmethoxycarbonyl-n-hexylamino, N-ethoxycarbonyl-methylamino, N-ethoxycarbonyl-ethylamino, N-cyclopropyloxycarbony1-methylamino, N-cyclopropyloxycarbonyl-ethylamino, N-cyclopropy1oxycarbony1-n-propylamino, N-cyclobuty1oxycarbonyl-methylamino, N-cyclobutyloxycarbonylisopropylamino, N-cyclopentyloxycarbony1-methylamino, Ncyclopentyloxycarbonyl-ethylamino, N-cyclohexyloxycarbonyl-methylamino, N-cyclohexyloxycarbonylethylamino, N-cycloheptyloxycarbonyl-methylamino, Ncyclopentylmethyloxycarbonyl-methylamino, Ncyclopentylmethyloxycarbony1 -ethylamino, Ncyclohexylmethyloxycarbonyl-methylamino, Ncyclohexylmethyloxycarbonyl-ethylamino, Ncycloheptylmethyloxycarbonyl-methylamino, Ncycloheptylmethyloxycarbonyl-ethylamino, N- (2cyclopentylethyloxy)-carbonyl-methylamino, N-(2cyclopentylethyloxy)-carbony1-ethylamino, N-(2cyclohexylethyloxy)-carbonyl-methylamino, N-(2cyclohexylethyloxy)-carbony1-ethylamino, N- (2cycloheptylethyloxy)-carbony1-methylamino, N-(2cycloheptylethyloxy) -carbonyl-ethylamino, Nphenoxycarbonyl-methylamino, N-phenoxycarbonylethylamino, N-phenoxycarbonyl-isopropylamino, Nbenzyloxycarbony1-methylamino, N-benzyloxycarbonylethylamino, N-benzyloxycarbonyl-isopropylamiho, N-(2phenylethoxy,-carbonyl-methylamino, N-(2-phenylethoxy, carbonyl-ethylamino, N-(2-phenylethoxy)-carbonylisopropylamino, N(3-phenylpropoxy)-carbonyl-methylamino, N-(3phenylpropoxy)-carbonyl-ethylamino, N-(3-phenylpropoxy)carbonyl-isopropylamino, N-methoxycarbony1cyclopropylamino, N-methoxycarbonyl-cyclobutylamino, Nmethoxycarbonyl-cyclopentylamino, N-methoxycar bony1cyclohexylamino, N-methoxycarbonyl-cycloheptylamino, Nethoxycarbonyl-cyclopropylamino, N-ethoxycarbonylcyclobutylamino, N-ethoxycarbonyl-cyclopentylamino, N17 ethoxycarbonyl-cyclohexylamino, N-ethoxycarbonylcycloheptylamino, N-methoxycarbonylcyclopropylmethylamino, N-methoxycarbony1cyclobutylmethylamino, N-methoxycarbony15 cyclopentylmethylamino, N-methoxycarbonylcyclohexylmethylamino, N-methoxycarbonylcycloheptylmethylamino, N-ethoxycarbonylcyclopropylmethylamino, N-ethoxycarbonylcyclobutylmethylamino, N-ethoxycarbonyl10 cyclopentylmethylamino, N-ethoxycarbonylcyclohexylmethylamino, N-ethoxycarbonylcycloheptylmethylamino, N-methoxycarbonyl-(2cyclopropylethyl)-amino, N-methoxycarbonyl-(2 cyclobutylethyl)-amino, N-methoxycarbonyl-(215 cyclopentylethyl)-amino, N-methoxycarbonyl-(2 cyclohexylethyl)-amino, N-methoxycarbonyl-(2cycloheptylethyl)-amino, N-ethoxycarbonyl-(2cyclopropylethyl)-amino, N-ethoxycarbonyl-(2cyclobutylethyl)-amino, N-ethoxycarbonyl-(220 cyclopentylethyl)-amino, N-ethoxycarbonyl-(2 cyclohexylethyl)-amino, N-ethoxycarbonyl-(2cycloheptylethyl)-amino, N-methoxycarbonyl-(3cyclopropylpropy1)-amino, N-methoxycarbony1-(3cyclobutylpropyl)-amino, N-methoxycarbonyl-(325 cyclopentylpropyl)-amino, N-methoxycarbonyl-(3cyclohexylpropyl)-amino, N-methoxycarbonyl-(3cycloheptylpropy 1.) -amino, N-ethoxycarbonyl- (3cyclopropylpropyl)-amino, N-ethoxycarbonyl-(3cyclobutylpropy1)-amino, N-ethoxycarbonyl-(330 cyclopentylpropyl)-amino, N-ethoxycarbonyl-(3cyclohexylpropy1)-amino, N-ethoxycarbonyl-(3cycloheptylpropyl)-amino, N-phenoxycarbonylcyclopropylamino, N-phenoxycarbonyl-cyclobutylamino, Nphenoxycarbonyl-cyclopentylamino, N-phenoxycarbonyl35 cyclohexylamino, N-phenoxycarbonyl-cycloheptylamino, Nbenzyloxycarbony1-cyclopropylamino, N-benzyloxycarbonylcyclobutylamino, N-benzyloxycarbonyl-cyclopentylamino, N-benzyloxycarbonyl-cyclohexylamino, Nbenzyloxycarbonyl-cycloheptylamino, N-(2-phenylethoxy)carbonyl-cyclopropylamino, N-(2-phenylethoxy) -carbonylcyclobutylamino, N-(2-phenylethoxy)-carbonylcyclopentylamino, N-(2-phenylethoxy)-carbony1cyclohexylamino, N- (2-phenylethoxy)-carbony1cycloheptylamino, N-(3-phenylpropoxy)-carbonylcyclopropylamino, N- ( 3 -phenylpropoxy) -carbonylcyclobutylamino, N-(3-phenylpropoxy)-carbonylcyclopentylamino, N-(3-phenylpropoxy)-carbonylcyclohexylamino, N-(3-phenylpropoxy)-carbonylcycloheptylamino, N-methylsulphonyl-cyclopropylamino, Nethylsulphonyl-cyclobutylamino, N-n-propylsulphonylcyclopentylamino, N-ethylsulphonyl-cyclohexylamino, Nmethylsulphonyl-cycloheptylamino, N-phenoxycarbonylcyclopropy lmethylamino, N-phenoxycarbony 1cyclobutylmethylamino, N-phenoxycarbonylcyclopenty lmethylamino, N-phenoxycarbony1cyclohexylmethylamino, N-phenoxycarbony1cycloheptylmethylamino, N-benzyloxycarbonylcyclopropylmethylamino, N-benzyloxycarbonylcyclobutylmethylamino, N-benzyloxycarbonylcyc 1 opentylmethylamino, N-benzyloxycarbonylcyclohexylmethylamino, N-benzyloxycarbony1cyclohepty lmethylamino, N- (2-pheny lethoxy carbonyl) . cyclopropy lmethylamino, N- (2-pheny lethoxy carbonyl) cyclobuty lmethylamino, N-(2-phenylethoxycarbonyl)cyclopenty lmethylamino, N- ( 2 -phenylethoxycarbonyl) cyclohexy lmethylamino, N- (2 -phenylethoxycarbonyl) cycloheptylmethylamino, N- (3 -phenylpropoxycarbonyl) cycl opropylmethylamino, N- (3 -phenylpropoxycarbonyl) cyclobuty lmethylamino, N- (3 -phenylpropoxycarbonyl) cyclopenty lmethylamino, N- ( 3-phenylpropoxycarbonyl) cyclohexy lmethylamino, N- (3 -phenylpropoxycarbonyl) cyclohepty lmethylamino, N-methy 1 sulphonyl cyclopropy lmethylamino, N-ethylsulphonylcyclobutylmethylamino, N-methylsulphonyl19 cyclopentylmethylamino, N-ethylsulphonylcyclohexylmethylamino, N-isopropylsulphonylcycloheptylmethylamino, N-phenoxycarbonyl-(2cyclopropylethyl)-amino, N-phenoxycarbonyl-(25 cyclobutylethyl)-amino, N-phenoxycarbonyl-(2cyclopentylethyl)-amino, N-phenoxycarbonyl-(2cyclohexylethyl)-amino, N-phenoxycarbonyl-(2cycloheptylethyl)-amino, N-benzyloxycarbonyl-(2cyclopropylethyl)-amino, N-benzyloxycarbonyl-(210 cyclobutylethyl)-amino, N-benzyloxycarbonyl-(2cyclopentylethyl)-amino, N-benzyloxycarbonyl-(2cyclohexylethyl)-amino, N-benzyloxycarbonyl-(2cycloheptylethyl)-amino, N-(2-phenylethoxycarbonyl)-(2cyclopropylethy1)-amino, N- (2-phenylethoxycarbonyl)-(215 cyclobutylethyl)-amino, N-(2-phenylethoxycarbonyl)-(2cyclopentylethyl)-amino, N-(2-phenylethoxycarbonyl)-(2cyclohexylethyl)-amino, N-(2-phenylethoxycarbonyl)-(2cycloheptylethyl)-amino, N- (3-phenylpropoxycarbonyl)-(2 cyclopropylethyl)-amino, N- (3-phenylpropoxycarbonyl)-(2 cyclobutylethyl)-amino, N-(3-phenylpropoxycarbonyl)-(2cyclopentylethyl)-amino, N-(3-phenylpropoxycarbonyl)-(2 cyclohexylethyl)-amino, N-(3-phenylpropoxycarbonyl)-(2cycloheptylethyl)-amino, N-methylsulphonyl-(2cyclopropylethyl)-amino, N-ethylsulphonyl-(225 cyclobutylethyl)-amino, N-isopropylsulphonyl-(2cyclopentylethyl)-amino, N-methylsulphonyl-(2cyclohexylethyl)-amino, N-methylsulphonyl-(2cycloheptylethyl)-amino, N-phenoxycarbonyl-( 3 cyclopropylpropyl)-amino, N-phenoxycarbonyl-(330 cyclobutylpropyl)-amino, N-phenoxycarbonyl-(3cyclopentylpropy1)-amino, N-phenoxycarbonyl-(3cyclohexylpropyl)-amino, N-phenoxycarbonyl-(3cycloheptylpropyl)-amino, N-benzyloxycarbonyl-(3cyclopropylpropyl)-amino, N-benzyloxycarbonyl-(3- . cyclobutylpropyl)-amino, N-benzyloxycarbonyl-(3cyclopentylpropyl)-amino, N-benzyloxycarbonyl-(3cyclohexylpropyl)-amino, N-benzyloxycarbonyl-(320 cycloheptylpropyl)-amino, N-(2-phenylethoxycarbonyl) -(3cyclopropylpropyl) -amino, N-(2-phenylethoxycarbonyl) -(3cyclobutylpropyl) -amino, N- (2-phenylethoxycarbonyl)-(3cyclopentylpropy 1) -amino, N- (2-phenylethoxycarbonyl )-(3cyclohexylpropyl) -amino, N- (2-phenylethoxycarbonyl)-(3cycloheptylpropyl) -amino, N- (3-phenylpropoxycarbony 1) (3-cyclopropylpropy1)-amino, N-(3pheny lpropoxycarbony 1 )-(3 -cyclobuty lpropyl) -amino, N- (3 pheny lpropoxycarbony 1 )-(3 -cyclopentylpropyl) -amino, N(3 -phenylpropoxycarbony 1 )-(3 -cyclohexylpropy1) -amino, N(3 -phenylpropoxycarbonyl )-(3 -cyclohepty lpropyl) -amino, N-methylsulphonyl- (3 -cyclopropylpropy 1) -amino, Nethylsulphonyl- (3-cyclobutylpropyl) -amino, Nisopropylsulphonyl- (3-cyclopentylpropyl) -amino, Nmethylsulphonyl- (3-cyclohexylpropyl) -amino, Nmethylsulphonyl- (3-cyclohepty lpropyl)-amino, N-benzoylcyclopropylamino, N-benzoyl-cyclobutylamino, N-benzoylcyclopentylamino, N-benzoyl-cyclohexylamino, N-benzoylcycloheptylamino, N-phenylacetyl-cyclopropylamino, Nphenylacetyl-cyclobutylamino, N-phenylacetylcyclopentylamino, N-phenylacetyl-cyclohexylamino, Nphenylacetyl-cycloheptylamino, N-phenylsulphonylcyclopropylamino, N-phenylsulphonyl-cyclobutylamino, Nphenylsulphonyl-cyclopentyl amino, N-phenylsulphonylcyclohexylamino, N-phenylsulphonyl-cycloheptylamino, Nbenzoyl-cyclopropylmethylamino, N-benzoylcyclobutylmethylamino, N-benzoyl-cyclopentylmethylamino, N-benzoyl-cyclohexylmethylamino, N-benzoylcycloheptylmethylamino, N-phenylacetylcyclopropylmethylamino, N-phenylacetyl-cyclobutylmethylamino, N-phenylacetyl-cyclopentylmethylamino, Nphenylacetyl-cyclohexylmethylamino, N-phenylacetylcycloheptylmethylamino, N-phenylsulphonyl-cyclopropylmethy lamino, N-phenylsulphonyl-cyclobuty lmethylamino, Nphenylsulphonyl-cyclopentylmethylamino, N-phenylsulphonyl-cyclohexylmethylamino, N-phenylsulphony1cycloheptylmethylamino, N-benzoyl- (2-cyclopropyl-ethyl) 21 amino, N-benzoyl-(2-cyclobutylethyl)-amino, N-benzoyl(2-cyclopentylethyl)-amino, N-benzoyl-(2cyclohexylethyl) -amino, N-benzoyl-(2-cycloheptyl-ethyl) amino, N-phenylacetyl- (2-cyclopropylethyl) -amino, N5 phenylacetyl-(2-cyclobutylethyl)-amino, N-phenyl-acetyl (2-cyclopentylethyl)-amino, N-phenylacetyl-(2cyclohexylethyl)-amino, N-phenylacetyl-(2-cycloheptylethyl) -amino, N-phenylsulphonyl- (2-cyclopropylethyl ) -amino, N-phenylsulphonyl- (2-cyclobutylethyl) 10 amino, N-phenylsulphonyl-(2-cyclopentylethyl)-amino, Nphenylsulphonyl- (2-cyclohexylethyl) -amino, N-phenylsulphonyl- (2 -cycloheptylethyl) -amino, N-benzoy 1- (3 cyclopropylpropy1)-amino, N-benzoyl-(3-cyclobutylpropyl ) -amino, N-benzoyl -(3 -cyclopentylpropy1) -amino, N benzoyl-(3-cyclohexylpropyl)-amino, N-benzoyl-(3cycloheptylpropyl)-amino, N-phenylacetyl-(3cyclopropylpropy 1) -amino, N-phenylacetyl -(3 -cyclobutyl propyl)-amino, N-phenylacetyl-(3-cyclopentylpropy1)amino, N-phenylacetyl- (3-cyclohexylpropyl) -amino, N2Q phenylacetyl-(3-Gyclohepty lpropyl)-amino, N-phenylsulphonyl- (3-cyclopropylpropyl) -amino, N-phenylsulphonyl-(3-cyclobutylpropyl)-amino, N-phenylsulphonyl- (3-cyclopentylpropyl) -amino, N-phenylsulphonyl- (3-cyclohexylpropyl)-amiho, N-phenyl25 sulphonyl-(3-cycloheptylpropyl)-amino, N-acetylcyclopropylamino, N-acetyl-cyclobutylamino, N-acetylcyclopentylamino, N-acetyl-cyclohexylamino, N-acetylcycloheptylamino, N-acetyl-cyclopropylmethylamino; Nacetyl -cyclobutylmethylamino, N-acetyl-cyclopenty1 30 methylamino, N-acety 1 -cyclohexylmethylamino, N-acetylcycloheptylmethylamino, N-acetyl- (2 -cyclopropylethyl) amino, N-acetyl-(2-cyclobutylethyl)-amino, N-acetyl-(2cyclopentylethyl)-amino, N-acetyl-(2-cyclohexylethyl)amino, N-acetyl-(2-cyclohepty lethyl)-amino, N-acetyl-(3 cyclopropylpropyl) -amino, N-acetyl- ( 3 -cyclobutylpropy 1) amino, N-acetyl-(3-cyclopentyl-propyl)-amino, N-acetyl(3-cyclohexylpropyl)-amino, N-acetyl-(322 cycloheptylpropyl)-amino, N-acetyl-benzyl-amino, Nacetyl-(2-phenylethyl,-amino, N-acetyl-(3-phenylpropyl) amino, N-benzoyl-benzylamino, N-benzoyl-(2-phenylethyl) amino, N-benzoyl-(3-phenyl-propyl)-amino, Nmethylsulphonyl-benzylamino, N-methyl-sulphonyl- (2phenylethyl)-amino, N-methylsulphony1-(3-phenylpropyl)amino, carboxy, methoxycarbonyl, ethoxycarbonyl, npropoxycarbonyl, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, n-butylaminocarbonyl, n-pentylaminocarbonyl, dimethyl aminocarbonyl, diethylaminocarbony1, diisopropylaminocarbony 1, cyclopropylaminocarbony1, cyclobutyl aminocarbonyl, cyclopentylaminocarbonyl, cyclohexy laminocarbony 1, cycloheptylaminocarbonyl, cyclopenty lmethylaminocarbonyl , cyclohexylmethylaminocarbonyl , cyclohepty lmethylaminocarbonyl, 2-cyclohexylethyl-aminocarbonyl, phenylaminocarbony1, fluorophenylaminocarbonyl, chlorophenylaminocarbonyl, bromophenylaminocarbonyl, methylphenylaminocarbonyl, ethylphenylaminocarbony1, isopropylphenylaminocarbonyl, methoxyphenylaminocarbonyl, ethoxyphenylaminocarbonyl, isopropoxyphenylaminocarbony 1, n-butoxyphenyl aminocarbonyl benzylaminocarbonyl, (2-phenylethyl) -aminocarbonyl, dimethylaminocarbonyl, diethylaminocarbony 1, diisopropylaminocarbonyl, N-methylethylaminocarbonyl, N methyl-n-propylaminocarbonyl, N-methyl-n-butylaminocarbonyl, aminoacetylamino, N-methoxycarbonyl-aminoacetylamino, N-ethoxycarbonyl-aminoacetylamino, Nisopropoxycarbonyl-aminoacetylamino, aminocarbonylamino methylaminocarbony lamino, dimethyl aminocarbonylamino, N methylaminocarbonyl-methylamino, N- (dimethylaminocarbonyl )-methylamino, N-dimethylaminocarbonylethylamino, N-dimethylaminocarbonyl-isopropylamino, N(dimethylaminocarbony1)-n-pentylamino, Nmethylaminocarbonyl-ethylamino, N-methylaminocarbonyl-n pentylamino, N-methylaminocarbonyl-n-hexylamino, Nmethylaminocarbonyl-n-octylamino, N-methylaminocar35 bonyl-n-dodecylamino, N-methylaminocarbonyl-cyclohexylamino, ethylaminocarbonylamino, N-ethylaminocarbonylmethylamino, N-ethylaminocarbonyl-ethylamino, Nethylaminocarbonyl-n-hexylamino, N-ethylaminocarbonyl-n5 octylamino, N-ethylaminocarbonyl-n-dodecylamino, Nethy1aminocarbonyl-cy clohexylamino, diethylaminocarbonylamino, N- (diethylaminocarbonyl) methylamino, N-(diethylaminocarbonyl)-ethylamino, N(diethylaminocarbonyl)-n-butylamino, N-(diethylaminoΊ q carbonyl)-n-hexylamino, N- (diethylaminocarbonyl,-noctylamino, N-(diethylaminocarbonyl)-n-dodecylamino, isopropylaminocarbonylamino, N-isopropylaminocarbonylmethylamino, n-butylaminocarbonylamino, N-(n-butylamino carbonyl)-methylamino, N-(n-butylaminocarbonyl)-ethy115 amino, N-( n-buty laminocarbonyl) -isopropylamino, N-(nbutylaminocarbonyl) -n-butylamino, N- (n-butylaminocarbonyl)-n-hexylamino, N-(n-butylaminocarbonyl)-n-octylamino, N-(n-butylaminocarbonyl)-n-dodecylamino, N- (nbutylaminocarbonyl)-cyclohexylamino, N-(di-(n-butyl),. aminocarbonyl)-amino, N-(di-(n-butyl)-aminocarbonyl)methylamino, N-(di-(n-butyl)-aminocarbonyl,-ethylamino, N-(di-(n-butyl)-aminocarbonyl)-n-butylamino, N-(di-inbutyl )-aminocarbonyl)-n-hexylamino, N- (di-(n-butyl)aminocarbonyl)-n-octylamino, N-(di-(n-butyl)aminocarbonyl)-n-dodecylamino, N—(n-pentyl- 0 aminocarbonyl) -ethylamino, N- (n-hexylaminocarbonyl) ethylamino, N-(n-octylaminocarbonyl)-ethylamino, N-(ndodecylaminocarbonyl)-ethylamino, n-hexylaminocarbonylamino, n-octylaminocarbonylamino, n-dodecylaminocarbonylamino, N-(n-hexylaminocarbonyl)-nbutylamino, N-(n-hexylaminocarbonyl)-n-pentylamino, N(n-hexylaminocarbonyl)-n-hexylamino, N-(n-hexylaminocarbony1)-n-octylamino, N- (n-hexylaminocarbonyl)-n dodecylamino, N-(n-octylaminocarbonyl)-n-butylamino, Ni5 (n-octylaminocarbonyl)-n-pentylamino, N-(n-octylaminocarbony1)-n-hexylamino, N- (n-octylaminocarbonyl)-n octylamino, N-(n-octylaminocarbonyl)-n-dodecylamino, N24 (n-dodecylaminocarbonyl)-n-butylamino, N-(n-dodecylaminocarbony1)-n-pentylamino, N-(n-dodecylaminocarbonyl )-n-hexylamino, N-(n-dodecylaminocarbonyl)-noctylamino, N-(n-dodecylaminocarbonyl)-n-dodecylamino, N—(n-hexylaminocarbonyl)-cyclohexylamino, N-(n-octylaminocarbonyl)-cyclohexylamino, N—(n-dodecylaminocarbonyl )-cyclohexylamino, di-(n-hexyl)-aminocarbony lamino , N- (di-(n-hexyl)-aminocarbonyl)methylamino, N-(methyl-(n-hexyl)-aminocarbonyl)-amino, N-cyclohexylaminocarbonyl-n-pentylamino, N-cyclohexylaminocarbonyl-n-hexylamino, N-cyclohexylaminocarbonyl-noctylamino, N-cyclohexylaminocarbonyl-n-dodecylamino, Ncyclohexylaminocarbonyl-cyclohexylamino, N-(ethyl-cyclohexylaminocarbonyl)-methylamino, N-(propyl-cyclohexy1aminocarbonyl) -methylamino, N- (n-buty 1-cyclohexylaminocarbony1)-methylamino, adamant-l-y1-aminocarbonylamino, 4-hydroxybutylaminocarbonylamino, 5-hydroxypentylaminocarbonylamino, 6-hydroxyhexylaminocarbonylamino, allylaminocarbonylamino, but-2-enylaminocarbonylamino, pent2-enylaminocarbonylamino, pent-3-enylaminocarbonylamino, crotylaminocarbonylamino, but-2-ynylaminocarbonylamino, pent-2-ynylaminocarbonylamino, pent-3-ynylaminocarbonylamino , tetrahydrof uran-2 -yl-aminocarbonylamino, tetrahydropyrah-2-yl-aminocarbonylamino, N-(ethyl-(n-pentyl)aminocarbonyl)-ethylamino, N-(methyl-cyclopentylaminocarbonyl)-methylamino, N-(methyl-cyclohexylaminocarbonyl)-ethylamino, cyclopropylaminocarbonylamino, Ncyclopropylaminocarbonyl-methylamino, cyclobutylaminocarbonylamino, N-cyclobutylaminocarbonyl-methylamino, cyclopentylaminocarbonylamino, N-cyclopentylaminocarbonyl-methylamino, cyclohexylaminocarbonylamino, Ncyclohexylaminocarbonyl-methylamino, N-cyclohexylaminocarbonyl-ethylamino, N-cyclohexylaminocarbonyl-npropylamino, N-cyclohexylaminocarbonyl-n-butylamino, Ncyclohexylaminocarbonyl-n-pentylamino, N-cyclohexylaminocarbony1-n-hexylamino, N-cyclohexylaminocarbony1-noctylamino, N-cyclohexylaminocarbonyl-n-dodecylamino, cycloheptylaminocarbonylamino, N-cycloheptylaminocarbonyl-methylamino, cyclopentylmethylaminocarbonylamino, N-cyclopentylmethy1aminocarbonyl-methylamino, cyclohexylmethylaminocarbonylamino, N-cyclohexylmethylaminocarbonyl-methylamino, benzylaminocarbonylamino, (2phenylethyl)-aminocarbonylamino, phenylaminocarbony1amino, fluorophenylaminocarbonylamino, chlorophenylaminocarbonylamino, bromophenylaminocarbonylamino, methylphenylaminocarbonylamino, ethylphenylaminocarbonylamino, isopropylphenylaminocarbonylamino, methoxyphenylaminocarbonylamino, ethoxyphenylaminocarbonylamino, isopropoxyphenylaminocarbonylamino, nbutoxyphenylaminocarbonylamino, aminothiocarbonylamino, methylaminothiocarbonylamino, N-methylaminocarbony1methylamino, N-methylaminocarbonyl-ethylamino, ethylaminothiocarbonylamino, N-ethylaminothiocarbonylmethylamino, N-ethylaminothiocarbonyl-ethylamino, Nethylaminothiocarbonyl-n-hexylamino, isopropylaminothiocarbonylamino, N-isopropylaminothiocarbonylmethylamino, allylaminothiocarbonylamino, but-2-enylaminothiocarbonylamino, pent-2-enylaminothiocarbony1amino, pent-3-enylaminothiocarbonylamino, crotylaminothiocarbony lamino, but-2-ynylaminothiocarbonylamino, pent-2-ynylaminothiocarbonylamino, pent-3-ynylaminothiocarbony lamino, tetrahydrofuran-2-yl-aminothiocarbonylamino, tetrahydropyran-2-yl-aminothiocarbonylamino, adamant-l-yl-aminothiocarbonylamino, cyclopropyl aminothiocarbonylamino, N-cyclopropylaminothiocarbonylmethylamino, cyclobutylaminothiocarbonylamino, N-cyclobutylaminothiocarbonyl-methylamino, cyclopentylaminothiocarbonylamino, N-cyclopentylaminothiocarbonylmethylamino, cyclohexylaminothiocarbonylamino, Ncyclohexylaminothiocarbonyl-methylamino, cycloheptylaminothiocarbonylamino, N-cycloheptylaminothiocarbonylmethylamino, cyclopentylmethylaminothiocarbonylamino, N cyclopentylmethylaminothiocarbonyl-methylamino, cyclohexylmethylaminothiocarbonylamino, N-cyclohexyl35 methylaminothiocarbonyl-methylamino, dimethylaminothiocarbonylamino, diethylaminothiocarbonylamino, N-(inhexyl) -aminothiocarbonyl)amino, N-(methyl-(n-hexyl)aminothiocarbonyl)amino, N-(dimethylamino-thiocarbonyl)5 methylamino, N-(dimethylaminothio-carbonyl) -npentylamino, N- (diethylaminothiocarbonyl) -methylamino, N-(diethylaminothiocarbonyl)-ethylamino, N-(di-inhexyl ) -aminothiocarbonyl) -methylamino, N- (di- (n-butyl) aminothiocarbonyl) -n-buty lamino, N- (methyl - ( n-hexyl) 10 aminothiocarbonyl) -methylamino, N- (ethyl - (n-pentyl) aminothiocarbonyl) -ethylamino, N- (methylcyclopentylaminothiocarbonyl) -methylamino, N- (methylcyclohexylaminothiocarbonyl) -ethylamino, benzylaminothiocarbonylamino, phenylaminothiocarbonyl15 amino, fluorophenylaminothiocarbony lamino, chlorophenylaminothiocarbonylamino, bromophenylaminothiocarbonylamino, methylphenylaminothiocarbonylamino, ethylphenylaminothiocarbonylamino, isopropylphenylaminothiocarbonylamino, methoxyphenylaminothiocarbony lamino, ethoxyphenylaminothiocarbonylamino, isopropoxyphenylaminothiocarbonylamino, n-butoxyphenylaminothiocarbonylamino, pyrrolidinocarbonylamino, piperidinocarbonylamino, hexamethyleneiminocarbonylamino, N-pyrro1 idinocarbonyl-methylamino, N-pyrrolidinocarbony 125 ethylamino, N-pyrrolidinocarbonyl-isopropylamino, Npyrrolidinocarbonyl-n-buty lamino, N-pyrrolidinocarbonyl-n-pentylamino, N-pyrrolidinocarbonyl-nhexy 1 amino, N-pyrrol idinocarbony 1 -n-octy lamino, Npyrrolidinocarbonyl-n-dodecylamino, N-pyrrolidino30 carbonyl-cyclopropylamino, N-pyrrolidinocarbonylcyclobutylamino, N-pyrrol idinocarbonyl-cyclopenty lamino, N-pyrrol idinocarbonyl-cyclohexylamino, N-pyrrol idinocarbony 1-cycloheptylamino , N-pyrrolidinocarbony1-cyclopropy lmethylamino, N-pyrrol idinocarbonyl-cyclobutyl35 methylamino, N-pyrrol idinocarbonyl-cyclopenty lmethylamino, N-pyrrolidinocarbonyl-cyclohexy lmethylamino, Npyrrol idinocarbony 1-cyclohepty lmethy lamino, N-pyrro27 lidinocarbonyl-(2-cyclopropylethyl)-amino, Npyrrolidinocarbonyl-( 2-cyclobutylethyl) -amino, Npyrrolidinocarbonyl-(2-cyclopentylethyl)-amino, Npyrrolidinocarbonyl-(2-cyclohexylethyl)-amino, N5 pyrrolidinocarbonyl-(2-cycloheptylethyl)-amino, Npyrrolidinocarbony1-(3-cyclopropylpropyl) -amino, Npyrrolidinocarbony1-(3-cyclobutylpropyl) -amino, Npyrrolidinocarbonyl-(3-cyclopentylpropyl) -amino, Npyrrol idinocarbony 1- (3 -cyclohexylpropyl) -amino, N10 pyrrolidinocarbonyl-(3-cycloheptylpropyl)-amino, Npyrrolidinocarbony1-phenylamino, N-pyrrolidino-carbonyl benzylamino, N-piperidinocarbony 1-methylamino, Npiperidinocarbony 1 -ethylamino, N-piperidinocarbonylisopropylamino, N-piperidinocarbonyl-n-buty lamino, N15 piperidinocarbonyl-n-pentylamino, N-piperidino-carbonyl n-hexylamino, N-piperidinocarbonyl-n-octylamino, Npiperidinocarbonyl-n-dodecylamino, N-piperidinocarbonyl cyclopropy lamino, N-piperidino-carbonyl-cyclobutylamino N-p iper idinocarbonyl-cyclopentylamino, N,0 piperidinocarbonyl-cyclohexylamino, Npiperidinocarbonyl-cycloheptylamino, N-piperidinocarbonyl-cycl opropy lmethylamino, N-piperidinocarbonylcyclobutylmethylamino, N-piperidinocarbonylcyclopentylmethylamino, N-piperidinocarbonyl,5 cyclohexy lmethylamino, N-piperidinocarbonylcycloheptylmethylamino, N-piperidinocarbonyl- (2cyclopropylethyl) -amino, N-piperidinocarbonyl- (2cyclobutylethyl)-amino, N-piperidinocarbonyl-(2cyclopentylethyl) -amino, N-piperidinocarbonyl- (20 cyclohexylethyl) -amino, N-piperidinocarbonyl- (2cycloheptylethyl) -amino, N-piperidinocarbonyl- (3cyclopropylpropyl) -amino, N-piperidinocarbonyl- (3cyclobutylpropyl)-amino, N-piperidinocarbonyl-(3cyclopentylpropyl) -amino, N-piperidinocarbonyl- (35 cyclohexy lpropyl) -amino, N-piperidinocarbonyl- (3 cycloheptylpropyl) -amino, N-piperidinocarbonylpheny lamino, N-piperidinocarbonyl-benzylamino, N28 hexamethyleneiminocarbonyl-methylamino, Nhexamethyleneiminocarbonyl-ethylamino, Nhexamethyleneiminocarbonyl-isopropylamino, Nhexamethyleneiminocarbonyl-n-butylamino, Nhexamethyleneiminocarbonyl-n-pentylamino, N— hexamethyleneiminocarbonyl-n-hexylamino, Nhexamethyleneiminocarbonyl-n-octylamino, Nhexamethyleneiminocarbonyl-n-dodecylamino, Nhexamethyleneiminocarbonyl-cyclopropylamino, Nhexamethyleneiminocarbonyl-cyclobutylamino, Nhexamethyleneiminocarbonyl-cyclopentylamino, Nhexamethyleneiminocarbonyl-cyclohexylamino, Nhexamethyleneiminocarbonyl-cycloheptylamino, Nhexamethyleneiminocarbonyl-cyclopropylmethylamino, Nhexamethyleneiminocarbonyl-cyclobutylmethylamino, Nh exame thy lene iminocarbonyl-cyclopenty lmethy lamino, N— hexamethyleneiminocarbonyl-cyclohexylmethylamino, Nhexamethyleneiminocarbonyl-cycloheptylmethylamino, Nhexamethyleneiminocarbonyl- (2 -cyclopropylethyl) -amino, N-hexamethyleneiminocarbonyl- (2-cyclobutylethyl) -amino, N-hexamethyleneiminocarbonyl- (2-cyclopentylethyl) -amino, N-hexamethyleneiminocarbonyl-(2-cyclohexyl ethyl) -amino, N-hexamethyleneiminocarbonyl- (2-cyclohepty lethyl) -amino, N-hexamethyleneiminocarbonyl- (3 -cyclopropy lpropyl) -amino, N-hexamethyleneiminocarbonyl*^- (3-cyclobutylpropyl) -amino, N-hexamethyleneiminocarbonyl- (3-cyclopenty lpropyl) -amino, N-hexamethyleneiminocarbonyl- (3-cyclohexy lpropyl) -amino, N-hexamethyleneiminocarbonyl- (3-cycloheptylpropyl) -amino, N-hexamethyleneiminocarbonyl-phenylamino, N-hexamethyleneiminocarbonyl-benzylamino, N-morpholinocarbony 1methylamino, N-morpholinocarbonyl-ethylamino, Nmorpholinocarbonyl-isopropylamino, N-mo rpho lino carbony 1n-butylamino, N-morpholinocarbonyl-n-pentylamino, Nmorpholinocarbonyl-n-hexylamino, N-morpholinocarbonyl-noctylamino, N-morpholinocarbonyl-n-dodecy lamino, Nmorphol inocarbonyl -cyclopropylamino, N-morphol inocarbonyl-cyclobutylamino, N-morpholinocarbonyl-cyclopentyl29 amino, N-morpholinocarbonyl-cyclohexylamino, Nmorphol inocarbonyl-cycloheptylamino, N-morphol inocarbonyl-cyclopropylmethylamino, N-morpholinocarbonylcyclobutylmethylamino, N-morpholinocarbonyl-cyclopentyl5 methylamino, N-morphol inocarbonyl-cyclohexylmethylamino, N-morphol inocarbonyl -cyclohepty lmethylamino, Nmoxpholinocarbonyl-(2-cyclopropylethyl) -amino, Nmorpholinocarbonyl- (2-cyclobutylethyl) -amino, Nmorpholinocarbonyl- (2-cyclopentylethyl) -amino, N10 morpholinocarbonyl-(2-cyclohexylethyl)-amino, Nmorpholinocarbonyl-(2-cycloheptylethyl) -amino, Nmorphol inocarbonyl- (3 -cyclopropylpropy 1) -amino, Nmorpholinocarbonyl-(3-cyclobutylpropyl) -amino, Nmorpholinocarbonyl- (3-cyclopentylpropyl) -amino, N15 morphol inocarbonyl- (3 -cyclohexy lpropy 1) -amino, Nmorpholinocarbonyl-(3-cycloheptylpropyl) -amino, Nmorpholinocarbonyl-phenylamino, N-morpholino-carbonylbenzylamino, phthalimino, 5-methoxy-phthalimino, 5,6dimethoxy-phthal imino, 6-methoxy-phthal imino, homophthal imino, z 4,4-dimethyl-homophthalimino, 7-methoxy homophthal imino, 6,7 -dimethoxy-homophthal imino, 7methoxy-4,4 -dimethyl -homophthal imino, 6,7 -dimethoxy-4, 4 dimethyl-homophthalimino, 1,2,3,6-tetrahydrophthalimino, hexahydrophthal imino, l-oxo-isoindolin-2-yl, 3,425 dimethyl-phthalimino, 4,5-dimethyl-t,2,3,6tetrahydrophthal imino, 4,5-dimethyl -hexahydrophthal imino 4.5- dimethyl-l-oxo-isoindolin-2-yl, 3,4-dimethoxyphthalimino, 4,5-dimethoxy-l,2,3,6-tetrahydrophthalimino 4.5- dimethoxy-hexahydrophthalimino, 4,5-dimethoxy-l-oxo30 isoindolin-2-yl, glutarimino, 3,3-tetramethyleneglutarimino, 3,3-pentamethylene-glutarimino, 2,2dimethyl-glutarimino, 3-methyl-glutarimino, 3,3-dimethyl glutarimino, 3-ethyl-glutarimino, hexafluoro-glutarimino 3-ethyl-3-methyl-glutarimino, 1,3-cyclopentanedicarbonyl imino, 2,4-dimethyl-glutarimino, 2,4-di-n-propy1glutarimino, endo-bicyclo[2,2,2]oct-5-ene-2,3dicarboxylic acid-imino, methyl-5-norbornene-2,3-di30 carboxylic acid-imino, 3,6-endoxo-l,2,3,6-tetrahydrophthal imino or 5-norbornene-endo-2,3-dicarboxyl ic acidimino group, for R2 the meanings mentioned above for Rx or lH-tetrazol5-yl, 2-imidazolidon-l-yl, 3-methyl-2-imidazolidon-l-yl, 3-ethyl-2-imidazolidon-l-yl, 3-n-propyl-2-imidazolidon-lyl, 3-isopropyl-2-imidazolidon-l-yl, 3-cyclopropy 1-2imidazolidon-l-yl, 3-cyclobutyl-2-imidazolidon-l-yl, 3cyclopentyl-2-imidazolidon-l-yl, 3-cyclohexyl-2imidazolidon-l-yl, 3-cycloheptyl-2-imidazolidon-l-yl, 3cyclopropylmethyl-2-imidazolidon-l-yl, 3-cyclobutylmethyl-2-imidazolidon-l-yl, 3-cyclopentylmethyl-2imidazolidon-l-yl, 3-cyclohexylmethyl-2-imidazolidon-lyl, 3-cycloheptylmethyl-2-imidazolidon-l-yl, 3-(2cyclopropylethyl)-2-imidazolidon-l-yl, 3-(2cyclobutylethyl)-2-imidazolidon-l-yl, 3-(2cyclopentylethyl) -2-imidazolidon-l-yl ,3-(2cyclohexylethyl) -2-imidazolidon-l-yl, 3-(2cycloheptylethyl) -2-imidazolidon-l-yl, 3-(3cyclopropylpropyl)-2-imidazolidon-l-yl, 3-(3cyclobutylpropyl) -2 -imidazol idon-l-yl ,3-(3cyclopentylpropyl)-2-imidazolidon-l-yl, 3-(3cyclohexylpropyl)-2-imidazolidon-l-yl, 3-(3cycloheptylpropyl) -2-imidazolidon-l-yl, 3-benzyl-2imidazolidon-l-yl, 3- (2-phenylethyl) -2-imidazolidon-l-yl, 3-(3-phertylpropyl)-2-imidazolidon-l-yl, 3,4,5>6tetrahydro-2-pyrimidon-l-yl, 3-methyl-3,4,5,6-tetrahydro2-pyrimidon-l-yl, 3-ethyl-3,4,5,6-tetrahydro-2-pyrimidonl-yl, 3-n-propyl-3,4,5,6-tetrahydro-2-pyrimidon-l-yl, 3isopropyl-3,4,5,6-tetrahydro-2-pyrimidon-l-yl, 3cyclopropyl-3,4,5,6-tetrahydro-2-pyrimidon-l-yl, 3cyclobutyl-3,4,5,6-tetrahydro-2-pyrimidon-l-yl, 3cyclopentyl-3,4,5,6-tetrahydro-2-pyrimidon-l-yl, 3cyclohexyl-3,4,5,6-tetrahydro-2-pyrimidon-l-yl, 3cycloheptyl-3,4,5,6-tetrahydro-2-pyrimidon-l-yl, 3cyclopropylmethyl-3,4,5,6-tetrahydro-2-pyrimidon-l-yl, 3 31 cyclobutylmethyl-3,4,5,6-tetrahydro-2-pyrimidon-l-yl, 3cyclopentylmethyl-3,4,5,6-tetrahydro-2-pyrimidon-l-yl, 3cyclohexylmethy1-3,4,5,6-tetrahydro-2-pyrimidon-l-yl, 3cycloheptylmethyl-3,4,5,6-tetrahydro-2-pyrimidon-l-yl, 3(2-cyclopropylethyl )-3,4,5,6-tetrahydro-2-pyrimidon-lyl, 3- (2-cyclobutylethyl )-3,4,5,6-tetrahydro-2-pyrimidon1- yl, 3-(2-cyclopentylethyl)-3,4,5,6-tetrahydro-2pyrimidon-l-yl, 3-(2-cyclohexylethyl)-3,4,5,6-tetrahydro2- pyrimidon-l-yl, 3-(2-cycloheptylethyl)-3,4, 5,6tetrahydro-2-pyrimidon-l-yl, 3- ( 3-cyclopropyl-propyl) 3,4,5,6-tetrahydro-2-pyrimidon-l-yl, 3-(3cyclobutylpropy 1 )-3,4,5,6-tetrahydro-2-pyrimidon-l-yl, 3 (3-cyclopentylpropyl )-3,4,5,6-tetrahydro-2-pyrimidon-lyl, 3-(3 -cyclohexylpropyl )-3,4,5,6-tetrahydro-2 pyrimidon-l-yl., 3-(3-cycloheptylpropyl) -3,4,5,6tetrahydro-2-pyrimidon-l-yl, 3-benzyl-3,4,5,6-tetrahydro2-pyrimidon-l-yl, 3-(2-phenylethyl)-3,4,5,6-tetrahydro-2pyrimidon-l-yl or 3-(3-phenylpropyl)-3,4,5,6-tetra-hydro2-pyrimidon-l-yl group, for R3 those of hydrogen, fluorine, chlorine or bromine atom, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.butyl, n-pentyl, n-hexyl, 1-methylpropyl, 1- methylbutyl, 2-methylbutyl, 3-methylbutyl, 1methylpentyl, 2-methylpentyl, 3-methylpentyl, 4methylpenty1, 1-ethylpropyl, Ι,ί-diethylethyl, methoxymethyl, ethoxymethyl, (2-hydroxyethoxy)-methyl, 2- methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl, methylmercaptomethyl, 2-methylmercapto-ethyl, 3methylmercapto-propyl, 4-methylmercapto-butyl, methylsulphinyl-methyl, 2-methylsulphinyl-ethyl, 3methylsulphinyl-propyl, 4-methylsulphinyl-butyl, methyl sulphonyl-methyl, 2-methylsulphonyl-ethyl, 3methylsulphonyl-propyl, 4-methyl sulphonyl-butyl, 2methylamino-ethyl, 3-methylamino-propyl, 4-methylaminobutyl, 2-dimethylamino-ethyl, 3-dimethylamino-propyl, 4dimethylamino-butyl, 5-dimethylamino-pentyl, 232 diethylamino-ethyl, 2-di-n-propylamino-ethyl, 2-(2hydroxyethoxy)-ethyl, 3-(2-hydroxyethoxy)-propy1, 2-(2methoxyethoxy)-ethyl, 2-(2-methoxyethoxy)-isopropyl, 3(2-methoxyethoxy)-propyl, 2-(2-ethoxyethoxy)-ethyl, 2-(2ethoxyethoxy)-isopropyl, 3-(2-ethoxyethoxy)-propyl, 2-(2isopropoxyethoxy)-ethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-me thoxy ethoxy, 2-ethoxy ethoxy, 2-isopropoxy ethoxy, 3methoxypropoxy, 3-isopropoxypropoxy, mercapto, methylmercapto, ethylmercapto, n-propylmercapto, isopropylmercapto, n-butylmercapto, benzyl, 2phenylethyl, 3-phenylpropyl, allyl, n-but-2-enyl, n-pent2-enyl, n-prop-l-enyl, n-but-l-enyl, n-pent-l-enyl, nbut-3-enyl, n-pent-3-enyl, n-pent-4-enyl, propargyl, nbut-3-ynyl, n-pent-3-ynyl, n-pent-4-ynyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, 2-cyclopentylethyl, 2-cyclohexyl-ethyl, 2-cycloheptylethyl, 3cyclopentylpropyl, 3-cyclohexylpropyl, phenyl, hydroxyphenyl, fl'uorophenyl, chlorophenyl, bromophenyl, methylphenyl, ethylphenyl, isopropylphenyl, methoxyphenyl, ethoxyphenyl, n-propoxyphenyl, nbutoxyphenyl, hydroxy, (imidazol-4-yl)methylamino, 2(imidazol-4 -yl) ethylamino, 3-( imidazol-4 -y 1) propy lamino, methylamino, ethylaniino, n-propylamino, isopropy lamino, n-butylamino, isobutylamino, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, cyclopentylaminocarbonyl, cyclohexylaminocarbonyl, cycloheptylaminocarbonyl, naphthyl, pyridyl; pyrimidyl, pyridazinyl, pyrazinyl, pyrazolyl, 1,3-dimethylpyrazolyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl or tetrazolyl group, and for Ra those of carboxy, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert.butoxycarbonyl, n33 pentoxycarbonyl, n-hexoxycarbonyl, benzyloxycarbonyl, 1phenylethoxycarbonyl, 2-phenyl-ethoxycarbonyl, 3-phenylpropoxycarbonyl, pivaloyloxymethoxycarbonyl, phthalidyloxycarbonyl, ethoxycarbonyloxyethoxycarbonyl, methoxymethoxycarbonyl, cyclohexyloxycarbonylmethoxycarbonyl, (1,3-dioxa-2-oxo-4-methyl-cyclopenten-5-yl)methoxycarbony1, amino, phthalimido, aminoacetylamino, methoxycarbonylaminoacetylamino, ethoxycarbonylaminoacetylamino, isopropoxycarbonylaminoacety lamino, nbutoxycarbonylaminoacetylamino, methylcarbonylamino, trifluoromethylcarbonylamino, ethyl carbony lamino, npropylcarbonylamino, isopropylcarbonylamino, cyclopentylcarbonylamino, cyclohexylcarbonylamino, cycloheptylcarbonylamino, pheny lcarbony lamino, fluorophenylcarbonylamino, chlorophenylcarbonylamino, bromophenyl carbonylamino, methylphenylcarbonylamino, ethylphenylcarbonylamino, isopropylphenylcarbonylamino, methoxyphenylcarbonylamino, ethoxyphenylcarbonylamino, n propoxypheny lcarbony lamino, benzy lcarbony lamino, 2phenylethylcarboriylamino, methylsulphonylamino, tr i f luoromethy 1 sulphonylamino, ethyl sulphonylamino, npropylsulphonylamino, isopropylsulphonylamino, phenylsulphonylamino, fluorophenylsulphonylamino, chlorophenylsulphonylamino, bromophenylsulphonylamino, methylphenylsulphonylamino, ethylphenylsulphonylamino, isopropylphenylsulphonylamino, methoxyphenylsulphonylamino, ethoxyphenylsulphonylamino, benzylsulphonylamino, cyano, aminomethyl, methylsulphonylaminomethyl, ethylsulphonylaminomethyl, n-propylsulphonylaminomethyl, phenylsulphonylaminomethyl, methylpheny1sulphonylaminomethyl , trif 1 uorome thy 1 sulphonyl ami nomethyl, methylsulphonylaminocarbonyl, ethylsulphonylaminocarbonyl, npropylsulphonylaminocarbonyl, isopropylsulphonylaminocarbonyl, n-butylsulphonylaminocarbonyl, trifluoromethyl sulphonylaminocarbonyl, perfluoro-n-butylsulphonylaminocarbonyl, phenylsulphonylaminocarbonyl, benzylsulphonylaminocarbonyl, 4-methylphenylsulphonylaminocarbonyl, 434 chlorophenylsulphonylaminocarbonyl, trifluoroacetylaminomethyl, lH-tetrazolyl or 1-(triphenylmethyl)tetrazolyl group.
Preferred compounds of the general formula I are those in which Rx denotes a hydrogen, fluorine or chlorine atom, a trifluoromethyl, hydroxy, benzyloxy, carboxy, cyano, amino, nitro, aminosulphonyl, methylaminosulphonyl, dimethylaminosulphonyl, trifluoromethylsulphonyloxy or tetrazolyl group, an alkyl group having l to 4 carbon atoms, wherein the methyl group may be additionally substituted by a hydroxy or alkylamino group having l to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, which may be substituted in the 2, 3 or 4 position by a hydroxy, alkoxy, alkylamino, dialkylamino or imidazolyl group and the alkyl substituent may contain 1 to 3 carbon atoms in each case, an alkanoyloxy group having 1 to 4 carbon atoms or a cycloalkylaminocarbonyloxy group having 5 to 7 carbon atoms in the cycloalkyl moiety, an amino group, which is substituted by a benzyl, Decalin, trifluoromethylcarbonyl, benzylcarbony1, benzyloxycarbonyl, 2-ethyl-5-methylcyclohexyloxy or tert.butoxycarbonylaminoacetyl group, by an alkyl group having 1 to 5 carbon atoms, by a cycloalkyl, cycloalkylalkyl, cycloalkoxycarbonyl, cycloalkylcarbonyl or cycloalkylalkanoyl group, wherein the cycloalkyl moiety may contain 5 to 7 carbon atoms, the alkyl moiety may contain 1 to 3 carbon atoms and the alkanoyl moiety may contain 1 to 3 carbon atoms, by an alkanoyl group having 1 to 6 carbon atoms, by an aminoalkanoyl or dialkylaminoalkanoyl group, in which the alkyl moiety and the alkanoyl moiety may each contain 1 to 3 carbon atoms, by an alkoxycarbonyl group having a total of 2 to 7 carbon atoms, by an alkylsulphonyl group having 1 to 4 carbon atoms or by a thiazolidin-3-ylcarbonyl group substituted by an alkoxycarbonyl group having a total of 2 to 4 carbon atoms, Ίθ a benzylamino or alkylamino group having 1 to 5 carbon atoms, which is substituted at the nitrogen atom additionally by a benzyl or cyclohexyl group, by an alkyl group having 1 to 3 carbon atoms, which may be substituted in the 2 or 3 position by an alkoxy group having 1 to 3 carbon atoms or by a phenylamino group, by an alkanoyl group having 1 to 5 carbon atoms, which may be substituted by an alkoxy group having 1 to 3 carbon atoms, by a cycloalkylcarbonyl group having a total of 6 to 8 carbon atoms or by an alkoxycarbonyl group having a total of 2 to 4 carbon atoms, a carbonyl group, which is substituted by an alkyl group which may be substituted in the 2- or 3-position by a hydroxy, alkoxycarbonyl or alkylamino group, by an alkylamino group with 1 to 5 carbon atoms which may be substituted by a carboxy group in the alkyl moiety, by an alkylamino group substituted by a phenylamino group in the 2- or 3-position, by a phenyl, alkoxy, amino, benzylamino, phenylethylamino, cycloalkylamino or cycloalkylalkylamino, in which the alkyl moiety may contain 1 to 3 carbon atoms and the cycloalkyl moiety may contain 5 to 7 carbon atoms, and additionally a Cx.s alkylamino group may be substituted at the nitrogen atom by an alkyl group having 1 to 4 carbon atoms, an aminocarbonylamino or aminothiocarbonylamino group, which may be monosubstituted, disubstituted or trisubstituted by an alkyl group having 1 to 12 carbon atoms, by an alkenyl or alkynyl group having 3 to 5 carbon atoms in each case, by a bicyclic or tricyclic alkyl group having 7 to 11 carbon atoms,by a cycloalkyl, cycloalkylalkyl or phenylalkyl group, wherein the substituents may be the same or different, and the alkyl moiety may contain 1 to 3 carbon atoms and the cycloalkyl moiety may contain 5 to 7 carbon atoms, and a methylene group in a cycloalkyl radical having 5 to 7 carbon atoms may be replaced by an oxygen atom, and an alkyl group may be substituted in the 4, 5 or 6 position by a hydroxy or trifluoroacetyl group, a cycloalkyleneiminocarbonylamino group having 4 to 6 carbon atoms in the cycloalkyleneimino moiety or a morpholinocarbonylamino group, which may both be substituted at the amino nitrogen by an alkyl group having 1 to 12 carbon atoms, by a cycloalkyl, cycloalkylalkyl or phenylalkyl group, in which the alkyl moiety may contain 1 to 3 carbon atoms and the cycloalkyl moiety may contain 5 to 7 carbon atoms, a phthal imino, homophthal imino, 2-carboxyphenylcarbonylamino, 2-carboxyphenylmethylamino, 2carboxyphenylmethylenecarbonylamino or 2carboxymethylenephenylcarbonylamino group, whilst a carbonyl group ih a phthal imino group may be replaced by a methylene group and a methylene group in a homophthal imino, 2-carboxyphenylmethylenecarbonylamino or: 2-carboxymethylenephenylcarbonylamino group may be substituted by one or two alkyl groups, and additionally the above-mentioned phenyl nuclei may be mono- or disubstituted by alkyl or alkoxy groups, whilst the substituents may be identical or different, and at the same time they may be partially or wholly hydrogenated, a bicycloalkane-3-carboxylic acid amino or bicycloalkene-3r carboxylic acid amino group substituted by a carboxy group in the 2-position, a bicycloalkane-2,3-dicarboxylic acid imino or bicycloalkene-2,3-dicarboxylic acid imino group, wherein the bicycloalkane and bicycloalkene parts each contain 9 or 10 carbon atoms, may be substituted by 1, 2 or 3 methyl groups and an endomethylene group may be replaced by an oxygen atom, a glutaric acid imino or 3carboxy-n-propylene-carbonyl group wherein the npropylene group may be perfluorinated, substituted by one or two alkyl groups or by a tetramethylene or pentamethylene group, or a 5,7-dioxa-lH,3H-imidazo[l,5-c]thiazolyl group, a 2imidazolidon-l-yl group optionally substituted in the 3 position by an alkyl group having 1 to 3 carbon atoms, or a 3,4,5,6-tetrahydro-2-pyrimidon-l-yl group, R2 denotes a hydrogen, fluorine or chlorine, a methyl, hydroxy or methoxy group, or Rt and R2 together with the two ortho position carbon atoms of the neighbouring phenyl ring denote a phenyl or l-alkyl-3,3-dialkyl-2,3-dihydro-pyrrol-2-one group, in which the alkyl moiety may contain 1 to 3 carbon atoms in each case, R3 denotes a hydrogen,, fluorine or chlorine atom, a hydroxy, benzyl or aminocarbonyl group, an alkyl group having 1 to 5 carbon atoms, wherein the methyl group may be additionally substituted by a hydroxy group, by an alkoxy, alkylsulphenyl, alkylsulphinyl or alkylsulphonyl group each having 1 to 3 carbon atoms, a cycloalkyl or cycloalkylalkyl group, in which the . cycloalkyl moiety may contain 5 to 7 carbon atoms and the alkyl moiety may contain 1 to 3 carbon atoms, an alkenyl or alkynyl group each having 3 to 5 carbon atoms, a phenylalkyl group having 1 to 3 carbon atoms, an alkylamino group having 1 to 4 carbon atoms, a pyridyl, furyl, thiazolyl or pyrazolyl group, which may be substituted by one or two methy1‘groups, R4 denotes an alkoxycarbonyl having a total of 1 to 5 carbon atoms, an amino, phthalimino, aminomethyl, carboxy, cyano, methylsulphonylaminocarbonyl, trifluoromethylsulphonylaminocarbonyl, benzenesulphonylaminocarbony 1, trifluorocarbonylaminomethy 1, trifluoromethylaminomethyl, tetrazolyl or 1-(triphenylmethyl)tetrazolyl group, Rs and Rg each denote a hydrogen atom or Rs and Re together with the two ortho position carbon atoms denote a phenyl group, and 1 and 3 isomer mixtures thereof and the addition salts thereof, in particular for pharmaceutical application their physiologically acceptable addition salts with inorganic or organic acids.
However, particularly preferred compounds of the general formula I are those in which Rx denotes an amino group, which is substituted by a benzyl, Decalin, trif luoromethylcarbonyl, benzy lcarbonyl, benzyloxycarbonyl; 2-ethyl-5-methylcyclohexyloxy or tert.butoxycarbonylaminoacetyl group,by an alkyl group having l to 5 carbon atoms, by acycloalkyl, cycloalkylalkyl, cycloalkoxycarbonyl, cycloalkylcarbonyl or cycloalkylalkanoyl group, wherein the cycloalkyl moiety may contain 5 to 7 carbon atoms, the alkyl moiety may contain 1 to 3 carbon atoms and the alkanoyl moiety may contain 1 to 3 carbon atoms, by an alkanoyl group having 1 to 6 carbon atoms, by an aminoalkanoyl or dialkylaminoalkanoyl group, in which the alkyl moiety and the alkanoyl moiety may each contain 1 to 3 carbon atoms, by an alkoxycarbonyl group having a total of 2 to 7 carbon atoms, by an alkylsulphonyl group having 1 to 4 carbon atoms or by a thiazolidin-3-ylcarbonyl group substituted by an alkoxycarbonyl group having a total of 2 to 4 carbon atoms, a benzylamino or alkylamino group having 1 to 5 carbon atoms, which is additionally substituted at the nitrogen atom by a benzyl or cyclohexy! group, by an alkyl group having 1 to 3 carbon atoms, which may be substituted in the 2 or 3 position by an alkoxy group having 1 to 3 carbon atoms or by a phenylamino group, by an alkanoyl group having 1 to 5 carbon atoms, which may be substituted by an alkoxy group having 1 to 3 carbon atoms, by a cycloalkylcarbonyl group having a total of 6 to 8 carbon atoms or by an alkoxycarbonyl group having a total of 2 to 4 carbon atoms, an aminocarbonylamino or aminothiocarbony lamino group, which may be monosubstituted, disubstituted or trisubstituted by an alkyl group having 1 to 12 carbon atoms, by an alkenyl or alkynyl group each having 3 to 5 carbon atoms, by a bicyclic or tricyclic alkyl group having 7 to 11 carbon atoms, by a cycloalkyl, cycloalkylalkyl or phenylalkyl group, wherein the substituents may be the same or different, and the alkyl moiety may contain 1 to 3 carbon atoms and the cycloalkyl moiety may contain 5 to 7 carbon atoms, and a methylene group in a cycloalkyl radical having 5 to 7 carbon atoms may be replaced by an oxygen atom, and an alkyl group may be substituted in the 4, 5 or 6 position by a hydroxy or trifluoroacetyl group, a cycloalkyleneiminocarbonylami.no group having 4 to 6 carbon atoms in the cycloalkyleneimino moiety or a morpholinocarbonylamino group, which may both be substituted at the amino nitrogen by an alkyl group having 1 to 12 carbon atoms, by a cycloalkyl, cycloalkylalkyl or phenylalkyl group, in which the alkyl moiety may contain 1 to 3 carbon atoms and the cycloalkyl moiety may contain 5 to 7 carbon atoms, a phthalimino, homophthalimino, 2-carboxypheny1carbonylamino, 2-carboxypheny lmethy lamino, 2carboxyphenylmethylenecarbonylamino or 2carboxymethylenephenylcarbonylamino group, whilst a carbonyl group in a phthalimino group may be replaced by a methylene group and a methylene group in a homophthalimino, 2-carboxyphenylmethylenecarbonylamino or 2 -carboxymethylenephenylcarbonylamino group may be substituted by one or two alkyl groups, and additionally the above-mentioned phenyl nuclei may be mono- or disubstituted by alkyl or alkoxy groups, whilst the substituents may be identical or different, and at the same time they may be partially or wholly hydrogenated, a bicycloalkane-3-carboxylic acid amino or bicycloalkene-3carboxylic acid amino group substituted by a carboxy group in the 2-position, a bicycloalkane-2,3-dicarboxylic acid imino or bicycloalkene-2,3-dicarboxylic acid imino group, wherein the bicycloalkane and bicycloalkene parts each contain 9 or 10 carbon atoms, may be substituted by 1, 2 or 3 methyl groups and an endomethylene group may be replaced by an oxygen atom, a glutaric acid imino or 3carboxy-n-propylene-carbonyl group wherein the npropylene group may be perfluorinated, substituted by one or two alkyl groups or by a tetramethylene or pentamethylene group, or a 5,7-dioxa-lH,3H-imidazo[l,5-c)thiazolyl group, Rz denotes a hydrogen atom, a methyl or hydroxy group, or Rx and R2 together with the two ortho position carbon atoms of the neighbouring phenyl ring denote a phenyl group, R3 denotes an alkyl group having 3 to 5 carbon atoms, an alkenyl or alkynyl group each having 3 to 5 carbon atoms, R4 denotes a carboxy, methylsulphonylaminocarbonyl, trifluoromethylsulphonylaminocarbonyl, benzenesulphonylaminocarbonyl, trifluorocarbonylaminomethyl, trifluoromethy laminomethyl or tetrazolyl group, R5 and R6 each denote a hydrogen atom or Rg and Rg together with the two ortho position carbon atoms denote a phenyl group, z' in particular those compounds of the general formula I in which R1 denotes an amino group, which is substituted by an alkanoyl group haying 1 to 6 carbon atoms, by an aminoalkanoyl or dialkylaminoalkanoyl group, in which the alkyl moiety and the alkanoyl moiety may each contain 1 to 3 carbon atoms, by an .alkoxycarbonyl group having a total of 2 to 7 carbon atoms or by a thiazolidin-3ylcarbonyl group substituted by an alkoxycarbonyl group having a total of 2 to 4 carbon atoms, a benzylamino or alkylamino group having 1 to 5 carbon atoms, which is substituted at the nitrogen atom by an alkanoyl group having 1 to 5 carbon atoms, which may be substituted by an alkoxy group having 1 to 3 carbon atoms, by a cycloalkylcarbonyl group having a total of 6 to 8 carbon atoms or by an alkoxycarbonyl group having a total of 2 to 4 carbon atoms, an aminocarbonylamino or aminothiocarbonylamino group,which may be monosubstituted, disubstituted or trisubstituted by an alkyl group having 1 to 8 carbon atoms, by an alkenyl or alkynyl group each having 3 to 5 carbon atoms, by a bicyclic or tricyclic alkyl group having 7 to ll carbon atoms, by a cycloalkyl, cycloalkylalkyl or phenylalkyl group, wherein the substituents may be the same or different, and the alkyl moiety may contain 1 to 3 carbon atoms and the cycloalkyl moiety may contain 5 to 7 carbon atoms, and a methylene group in a cycloalkyl radical having 5 to 7 carbon atoms may be replaced by an oxygen atom, and an alkyl group may be substituted in the 4, 5 or 6 position by a hydroxy or trifluoroacetyl group, a cycloalkyleneiminocarbonylamino group having 4 to 6 carbon atoms in the cycloalkyleneimino moiety or a morphol inocarbonylamino group, which may both be substituted at the amino nitrogen by an alkyl group having 1 to 8 carbon atoms, by a cycloalkyl, cycloalkylalkyl or phenylalkyl group, in which the alkyl moiety may contain 1 to 3 carbon atoms and the cycloalkyl moiety may contain 5 to 7 carbon atoms, a phthalimino, homophthalimino, 2-carboxyphenylcarbonylamino, 2-carboxyphenylmethylamino, 2carboxyphenylmethylenecarbonylamino or 2carboxymethylenephenylcarbonylamino group, whilst a carbonyl group in a phthalimino group may be replaced by a methylene group and a methylene group in a homophthalimino, 2-carboxyphenylmethylenecarbonylamino or 2-carboxymethylenephenylcarbonylamino group may be substituted by one or two alkyl groups, and additionally the above-mentioned phenyl nuclei may be mono- or disubstituted by alkyl or alkoxy groups, whilst the substituents may be identical or different, and at the same time they may be partially or wholly hydrogenated, a bicycloalkane-3-carboxylic acid amino or bicycloalkene-3carboxylic acid amino group substituted by a carboxy group in the 2-position, a bicycloalkane-2,3-dicarboxylic acid imino or bicycloalkene-2,3-dicarboxylic acid imino Ίθ group, wherein the bicycloalkane and bicycloalkene parts each contain 9 or 10 carbon atoms, may be substituted by 1, 2 or 3 methyl groups and an endomethylene group may be replaced by an oxygen atom, a glutaric acid imino or 3carboxy-n-propylene-carbonyl group wherein the npropylene group may be perfluorinated, substituted by one or two alkyl groups or by a tetramethylene or pentamethylene group, or a 5,7-dioxa-lH,3H-imidazo[l,5-c]thiazolyl group, R2 denotes a hydrogen atom, or Rx and R2 together with the two ortho position carbon atoms of the neighbouring phenyl ring denote a phenyl group, R3 denotes an alkyl group having 3 to 5 carbon atoms, an alkenyl or alkynyl group each having 3 to 5 carbon atoms, R4 denotes a carboxy or tetrazolyl group, Rs denotes a hydrogen atom, Re denotes a hydrogen atom or r5 and Rg together with the two ortho position carbon atoms denote a phenyl group. 1-isomer and 3-isomer mixtures thereof and addition salts thereof, in particular for pharmaceutical application their physiologically acceptable addition salts with inorganic or organic acids.
The novel compounds of the formula I are obtained in accordance with the invention by the following processes: a) cyclisation of a compound of the formula Y, in which Rx and Rj, are as hereinbefore defined, one of the radicals Xx or Yx is a group of the formula and the other of the radicals Xx or Yx is a group of the formula wherein R3* as hereinbefore defined for R3, with the exception of the fluorine, chlorine or bromine atom, the hydroxy, mercapto or aminocarbonyl group, wherein the latter may be substituted by an alkyl group having 1 to 3 carbon atoms or by a cycloalkyl group having 5 to 7 carbon atoms, Ra to Re are as hereinbefore defined, R7 denotes a hydrogen atom, a hydroxy group or an R3*CO group, wherein R3* is defined as above, Zx and Z2, which may be the same or different, denote optionally substituted amino groups or hydroxy or mercapto groups optionally substituted by lower alkyl groups, or Zx and Z2, together denote an oxygen or sulphur atom, an imino group optionally substituted by an alkyl group having 1 to 3 carbon atoms, an alkylenedioxy or alkylenedithio group each having 2 or 3 carbon atoms, but wherein one of the radicals Xx or Yx must be a group of the formula The cyclisation is advantageously carried out in a solvent or solvent mixture, such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycolmonomethylether, diethyleneglycoldimethyl ether, sulpholane, dimethylformamide, Tetralin or in an excess of the acylating agent used for the preparation of the compound of the general formula II, for example in the corresponding nitrile, anhydride, acid halide, ester or amide, for example at temperatures between 0 and 250 °C, but preferably at the boiling temperature of the reaction mixture, optionally in the presence of a condensation agent; such as phosphorusoxychloride, thionylchloride, sulphurylchloride, sulphuric acid, p-toluenesulphonic acid, methanesulphonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic anhydride, or optionally also in the presence of a base, such as potassium ethoxide or potassium tert.butoxide. However, cyclisation may also be carried out without a solvent and/or condensing agent.
However, the reaction is particularly advantageously carried out by preparing a compound of the formula II in the reaction mixture by reducing a corresponding onitroamino compound, optionally in the presence of a carboxylic acid of the formula Hg'COOH, or by acylation of a corresponding o-diamino compound. When the reduction of the nitro group is terminated at the hydroxylamine step, the N oxide of a compound of the formula I is obtained in the subsequent cyclisation. The N oxide thus obtained is then converted to a corresponding compound of the formula I by means of reduction.
The subsequent reduction of the N oxide of formula I obtained is preferably carried out in a solvent, such as water, water/ethanol, methanol, glacial acetic acid. ethyl acetate or dimethylformamide, with hydrogen in the presence of a hydrogenation catalyst, such as Raney nickel, platinum or palladium/carbon, with metals, such as iron, tin or zinc in the presence of an acid such as acetic acid, hydrochloric acid or sulphuric acid, with salts, such as iron (II) sulphate, tin (II) chloride or sodium dithionite, or with hydrazine in the presence of Raney nickel, at temperatures between 0 and 50 °C, but preferably at ambient temperature.
A 2-alkoxy compound of formula I optionally thus obtained, can then be converted to a corresponding 2hydroxy compound of formula I, optionally by means of hydrolysis, preferably in the presence of an acid, such Ί5 as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid or trichloroacetic acid, in a suitable solvent, such as water, water/methanol, ethanol, water/ethanol, water/isopropanol or water/dioxane, at temperatures between -10 and 120 °C, for example at 2q temperatures between 20 °C and the boiling temperature of the reaction mixture. b) For the preparation of the compounds of formula I, in which R3 represents the aromatic or heteroaromatic radicals mentioned hereinbefore for R3: Reaction of a phenylenediamine of the formula (in which Rx and R2 are as hereionbefore defined, one of the radicals X2 or Y2 denotes a group of the formula NH in which to R6 are as hereinbefore defined, and the other of the radicals X2 or Y2 denotes an amino group) with an aldehyde of the formula OCH -R3 (IV) in which R3 denotes an aromatic or heteroaromatic radical as hereinbefore defined for R3.
The reaction is preferably carried out in a suitable solvent, such as benzene, toluene, xylene, mesitylene or dimethylacetamide, in the presence of a oxidising agent, such as sulphur or air oxygen, at temperatures between 80 and 250 °C, preferably at the boiling temperature of the reaction mixture.
A 2-alkoxy compound of formula I optionally thus obtained can then be converted to a corresponding 2-hydroxy compound of formula I, optionally by means of hydrolysis, preferably in the presence of an acid, such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid or trichloroacetic acid, in a suitable solvent, such as water, water/methanol, ethanol, water/ethanol, water/isopropanol or water/dioxane, at temperatures between -10 and 120 °C, for example at temperatures between 20 °C and the boiling temperature of the reaction mixture. c) For the preparation of compounds of the formula I, in which at least one of the radicals Rlz Rz and/or R3 is one of the radicals containing a sulphinyl or sulphonyl group as hereinbefore defined for Rlf Rz and/or R3, and the remainder of the radicals Rlr Rz and/or R3 are as hereinbefore defined: Oxidation of a compound of the formula in which R4 to Re are as hereinbefore defined, at least one of the radicals R^, Rz' and/or R3' is one of the radicals containing a sulphur atom or a sulphinyl group as hereinbefore defined for Rx, Rz and/or R3, and 3Q the remainder of the radicals Rx, R2' and/or R3' have the meanings hereinbefore defined for Rx, Rz and/or R3.
The oxidation is preferably carried out in a solvent or solvent mixture, for example in water, water/pyridine, 35 acetone, glacial acetic acid, dilute sulphuric acid or trifluoroacetic acid, advantageously at temperatures between -80 and 100 °C, depending on the oxidising agent used.
For the preparation of a sulphinyl compound of the formula I, the oxidation is advantageously carried out using one equivalent of the oxidising agent used, for example using hydrogen peroxide in glacial acetic acid, trifluoroacetic acid or formic acid at 0 to 20 °C or in acetone at 0 to 60 °C, using a peracid, such as performic acid in glacial acetic acid or trifluoroacetic acid at 0 to 50 °C, or using m-chloroperbenzoic acid in methylene chloride or chloroform at -20 to 60 °C, using sodium metaperiodate in aqueous methanol or ethanol at -15 to 25°C, using bromine in glacial acetic acid or aqueous acetic acid, using N-bromosuccinimide in ethanol, using tert.butyl hypochlorite in methanol at -80 to -30 °C, using iodobenzodichloride in aqueous pyridine at 0 to 50 °C, using nitric acid in glacial acetic acid at 0 to 20 °C, using chromic acid in glacial acetic acid or in acetone at 0 to 20 °C, and using sulphuryl chloride in methylene chloride at -70 °C, the thioether-chlorine complex thus obtained is advantageously hydrolysed using aqueous ethanol.
For the preparation of a sulphonyl compound of the formula I, the oxidation is advantageously carried out using one or using two or more equivalents of the oxidising agent used, for example using hydrogen peroxide in glacial acetic acid, trifluoroacetic acid or in formic acid at 20 to 100 °C,or in acetone at 0 to 60 °C, using a peracid, such as performic acid or m-chloroperbenzoic acid in glacial acetic acid, trifluoroacetic acid, methylene chloride or chloroform at temperatures between 0 and 60 °C, using nitric acid in glacial acetic acid at 0 to 20 °C, using chromic acid or potassium permanganate in glacial acetic acid, water/sulphuric acid or in acetone at 0 to 20 °C. d) For the preparation of a compound of the formula I, in which R<, is a carboxy or amino group: Conversion of a compound of the formula in which Rx to R3, R5 and Re are as hereinbefore defined, and R«' is a group which can be converted to a carboxy group by means of hydrolysis, thermolysis or hydrogenolysis, or a group which can be converted to an amino group by means of hydrolysis, hydrogenolysis or transamidation.
For example, functional derivatives of the carboxy group, such as its unsubstituted or substituted amides, esters, thiolesters, orthoesters, iminoethers, amidines or anhydrides, the nitrile group or the tetrazolyl group, can be converted to a carboxy group by means of hydrolysis, esters of tertiary alcohols, for example tert.butylester, can be converted to a carboxy group by means of thermolysis, esters of aralkanols, for example benzyl ester, can be converted to a carboxy group by means of hydrogenolysis, acylamino groups, for example the benzoylamino or phthalimido group, can be converted to an amino group by means of hydrolysis and imino groups, for example the phthalimino group, can be converted to an amino group by means of transamidation.
The hydrolysis is advantageously carried out either in the presence of an acid, such as hydrochloric acid, sulphuric acid, phosphoric acid, trichloroacetic acid or trifluoroacetic acid, in the presence of a base, such as sodium hydroxide or potassium hydroxide, in a suitable solvent, such as water, water/methanol, ethanol, water/ethanol, water/isopropanol or water/dioxane, at temperatures between -10 °C and 120 °C, for example at temperatures between ambient temperature and the boiling temperature of the reaction mixture. During hydrolysis in the presence of an organic acid, such as trichloroacetic acid or trifluoroacetic acid, alcohol hydroxy groups, which are optionally present, may also be converted to a corresponding acyloxy group, such as the trifluoroacetoxy group.
If RJ in a compound of formula VI denotes a cyano or aminocarbonyl group, these groups may also be converted to the carboxy group using a nitrite, for example sodium nitrite, in the presence of an acid, such as sulphuric acid, this advantageously being used at the same time as solvent, at temperatures between 0 and 50 °C.
If Ra* in a compound of formula VI denotes, for example the tert-butyloxycarbonyl group, the tert.butyl group may also be cleaved thermally, optionally in a inert solvent, such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane, and preferably in the presence of a catalytic amount of an acid, such as ptoluenesulphonic acid, sulphuric acid, phosphoric acid or polyphosphoric acid, preferably at the boiling temperature of the solvent used, for example at temperatures between 40 °C and 100 °C.
If R/ in a compound of formula VI denotes, for example the benzyloxycarbonyl group, the benzyl group may also be cleaved hydrogenolytically in the presence of a hydrogenation catalyst, such as palladium/carbon, in a suitable solvent, such as methanol, ethanol. ethanol/water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at temperatures between 0 and 50 °C, for example at ambient temperature, and a hydrogen pressure of 1 to 5 bar. During the hydrogenolysis, other radicals may also be reduced at the same time, for example a nifro group to the amino group, a benzyloxy group to the hydroxy group, a vinylidene group to the corresponding alkylidene group or a cinnamic acid group to the corresponding phenylpropionic acid group, or may be replaced by hydrogen atoms, for example a halogen atom may be replaced by a hydrogen atom.
If R*· denotes a phthalimino group, this group may be converted particularly advantageously to an amino group, in the presence of a primary organic base, such as methylamine, ethylamine or propylamine, in a suitable solvent, such as methanol, ethanol, isopropanol, dimethylformamide, methanol/dimethylformamide or methanol/water, by transamidation at temperatures between 0 and 50 °C, but, preferably at ambient temperature. If Rx and/or Rz denote here one of the imino radicals mentioned hereinbefore, they are similarly converted to a corresponding amino group.
If Rx and/or Rz in a compound of formula VI represents one of the above-mentioned imino groups, this may also be partially hydrolysed during the reaction, for example into a 2-carboxyphenylcarbonylamino, 20carboxyphenylmethylamino, 2-carboxyphenylmethylenecarbonylamino or 2carboxymethylenephenylcarbonylamino group, whilst a methylene group in a 2-carboxyphenylmethylenecarbonylamino or 2-carboxymethylenephenylcarbonylamino group may be substituted by one or two alkyl groups, and additionally the above-mentioned phenyl nuclei may be mono- or disubstituted by alkyl or alkoxy groups, the substituents being identical or different, and at the same time they may be wholly or partially hydrogenated, a bicycloalkane-3-carboxylic acid amino or bicycloalkene-3carboxylic acid amino group substituted by a carboxy group in the 2-position, wherein the bicycloalkane and bicycloalkene moieties each contain 9 or 10 carbon atoms, may be substituted by 1, 2 or 3 methyl groups and an endomethylene group may be replaced by an oxygen atom, a 3-carboxy-n-propylenecarbonyl group wherein the npropylene group may be perfluorinated, substituted by one or two alkyl groups or substituted by a tetramethylene or pentamethylene group. e) Reaction of a benzimidazole of the formula H in which Ri to R3 are as hereinbefore defined, with a biphenyl compound of the formula in which R* to Rg are as hereinbefore defined, and Z3 is a nucleophilic leaving group, such as a halogen atom, for example a chlorine, bromine or iodine atom, or a substituted sulphonyloxy group, for example a methanesulphonyloxy, phenylsulphonyloxy or ptoluenesulphonyloxy group.
The reaction is advantageously carried out in a solvent or solvent mixture, such as methylene chloride, diethylether, tetrahydrofuran, dioxane, dimethylsulphoxide or benzene, optionally in the presence 1 q of an acid-binding agent, such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium tert.butoxide, triethylamine or pyridine, wherein the two latter agents may also be used at the same time as solvent, preferably at temperatures between 0 and 100 °C, Ί5 for example at temperatures between ambient temperature and 50 °C.
During the reaction, a mixture of the 1-isomer and 3isomer is preferably obtained. f) For the preparation of a compound of the formula I, in which Ra is a ΙΗ-tetrazolyl group: Cleaving a protective radical from a compound of the ,r formula in which Rx to r3, Rs and Re are as hereinbefore defined, and R4 is a ΙΗ-tetrazolyl group protected in the 1 position by a protective radical.
Suitable examples of a protective radical are the triphenylmethyl, tributyltin or triphenyltin group.
Cleaving a protective radical used is preferably carried out in the presence of a hydrogen halide, preferably in the presence of hydrogen chloride, in the presence of a base, such as sodium hydroxide or alcoholic ammonia, in a suitable solvent, such as methylene chloride, methanol, methanol/ammonia, ethanol or isopropanol, at temperatures between 0 and 100 °C, but preferably at ambient temperature, or even at elevated temperatures, if the reaction is carried out in the presence of alcoholic ammonia, for example at temperatures between 100 and 150 °C, preferably at temperatures between 120 and 140 °C. g) For the preparation of a compound of formula I, in which R<, is a ΙΗ-tetrazolyl group: Reaction of a compound of the formula (in which Rx to R3, Rj and Re are hereinbefore as defined with hydrazoic acid.
The reaction is preferably carried out in a solvent, such as benzene, toluene or dimethylformamide, at temperatures between 80 and 130 °C, preferably at 125 °C. The hydrazoic acid is thus particularly advantageously released during the reaction from an alkali azide, for example from sodium azide, in the presence of a weak acid, such as ammonium chloride. h) For the preparation of a compound of formula I, in which Rx and/or R2 is an aminocarbonylamino group, which may be monosubstituted, disubstituted or trisubstituted by a bicyclic or tricyclic alkyl group or by an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aralkyl or aryl group, wherein a methylene group in a cycloalkyl radical having 4 to 7 carbon atoms may be replaced by an oxygen atom: Reaction of a compound of the formula (in which R2 to R6 are as hereinbefore defined, and Re denotes a hydrogen atom, an alkyl group having 1 to 20 carbon atoms, an alkenyl or alkynyl group each having 3 to 5 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a cycloalkylalkyl group, in which the cycloalkyl moiety may contain 3 to 7 carbon atoms, the alkyl moiety may contain 1 to 3 carbon atoms and in a cycloalkyl moiety having 4 to 7 carbon atoms a methylene group may be replaced by an oxygen atom, a bicyclic or a hydroxy, alkyl or alkoxy group each carbon atoms) with a compound of the cw (XII) tricyclic alkyl group having 7 to 10 carbon atoms, an aryl or aralkyl group having 1 to 3 carbon atoms in the alkyl moiety, wherein the aryl group may be a phenyl group optionally substituted by a fluorine, chlorine or bromine atom, having 1 to 4 formula R Rs in which Rg, which may be the same or different, have the meanings mentioned above for Re, W is an oxygen or sulphur atom, Z4 is a nucleophilic leaving group, such as a chlorine or bromine atom, or also if at least one of the radicals Rg is a hydrogen atom, Z4 and Rg together are a nitrogen-carbon bond or a cycloalkyleneimino group having 4 to 6 carbon atoms, or a morpholino group.
The reaction is preferably carried out in a solvent, such as tetrahydrofuran, dioxane, ethylene chloride or benzene, optionally in the presence of an acid-binding agent, such as triethylamine or pyridine, advantageously at temperatures between 0 and 100 °C, preferably at temperatures between 20 and 80 °C. i) For the preparation of a compound of the formula I, in which Ra is a trifluoromethylcarbonylamino, trifluoromethylcarbonylaminomethyl, trifluoromethylsulphonylamino, trifluoromethylsulphonylaminomethyl or lH-tetrazolyl group, an alkylcarbonylamino, alkylcarbonylaminomethyl, arylcarbonylamino, airy lcarbony laminomethyl, aralkylcar59 bonylamino, aralkylcarbonylaminomethyl, alkylsulphonylamino, alkylsulphonylaminomethyl, arylsulphonylamino, arylsulphonylaminomethyl, aralkylsulphonylamino or aralkylsulphonylaminomethyl group, in which the alkyl moiety may contain 1 to 3 carbon atoms in each case: Acylation of a compound of the formula .,. (in which Rr to R3, Rs and Rg are as hereinbefore defined, and R*"' is an amino or aminomethyl group) using a compound of the formula HO -U -R10 (XIV) in which R10 denotes a trifluoromethyl group, an alkyl, aryl or __ aralkyl group, wherein the alkyl moiety may contain 1 to Zb . carbon atoms in each case, and U denotes a carbonyl or sulphonyl group, or using reactive derivatives thereof, such as acid halides, acid esters or acid anhydrides.
Suitable examples of reactive derivatives of a compound of the formula XIV are esters thereof, such as methyl, ethyl or benzyl esters, thioesters thereof, such as methylthio or ethylthio ester, halides thereof, such as the acid chlorides, anhydrides or imidazolides thereof.
The reaction is advantageously carried out in a solvent or solvent mixture, such as water, methylene chloride, chloroform, ether, tetrahydrofuran, dioxane or dimethylformamide, using a corresponding carboxylic acid in the presence an acid activating or a dehydrating agent, such as thienyl chloride, using anhydrides thereof, such as acetic anhydride, using esters thereof, such as ethyl acetate, using halides thereof, such as acetyl chloride or methanesulphonyl chloride, optionally in the presence of an inorganic or tertiary organic base, such as sodium hydroxide, potassium carbonate, triethylamine or pyridine, wherein the two latter bases may also serve as solvent at the same time, at temperatures between -25 and 100 °C, but preferably at temperatures between -10 and 80 °C. k) For the preparation of a compound of the formula I, in which R$ is an alkylsulphonylaminocarbonyl or perfluoroalkylsulphonylamino group each having 1 to 4 carbon atoms inthe alkyl moiety, or is a benzylsulphonylaminocarbonyl group: Reaction of a reactive derivative of a carboxylic acid of the formula in which Rx to R3, Rs and Rg are as hereinbefore defined, with a sulphonamide of the formula H2N -S02 -R„ (XVI) in which Ru is an alkyl or perfluoroalkyl group each having 1 to 4 carbon atoms, or is a benzyl group, or with alkali metal salt thereof.
Suitable reactive derivatives of a carboxylic acid of the formula XV, which may be prepared in the reaction mixture, are halides thereof, such as the chloride or bromide, or carbonate derivatives thereof, such as the imidazolcarbonyloxy or diphenylcarbamoyloxy derivative.
The reaction is advantageously carried out in a suitable solvent, such as methylene chloride, tetrahydrofuran, dioxane or dimethylsulphoxide, at temperatures between 0 and 180 °C, preferably between ambient temperature and 150 °C. However, the reaction may also be carried out in a melt. 1) For the preparation of a compound of the formula I, in which R2 is a 2-imidazolidon-l-yl or3,4,5,6-tetrahydro-2pyrimidon-l-yl group optionally substituted in the 3 position by an alkyl, cycloalkyl, cycloalkylalkyl or aralkyl group: (in which Rx, R3 and R4 to Rg are as hereinbefore defined, Hal is a chlorine, bromine or iodine atom, and n is the number 2 or 3) and, if required, subsequent reaction with a compound of the formula R12 -Hal (XVIII) in which R12 is an alkyl, cycloalkyl, cycloalkylalkyl or aralkyl group, and Hal is a chlorine, bromine or iodine atom.
Cyclisation and, if required, the subsequent alkylation, is advantageously carried out in a solvent, such as methanol, ethanol, benzene or dimethylsulphoxide, optionally in the presence of a phase transfer catalyst, such as benzyltriethylammonium bromide, in the presence of an acid-binding agent, such as sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride or potassium tert.butoxide, at temperatures between 20 and 100 °C, preferably at temperatures between 30 and 70 °C. m) For the preparation of compounds of the general formula I, in which Rx denotes an amino group, which is monosubstituted by a dialkylaminoalkanoyl, acyl, cycloalkoxycarbonyl, cycloalkylalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl or trifluoroacetyl group, by an alkylsulphonyl group having 1 to 4 carbon atoms, by an alkoxycarbonyl group having a total of 2 to 7 carbon atoms, or by a thiazolidin-3-ylcarbonyl group substituted by an alkoxycarbonyl group, an alkylamino group having 1 to 6 carbon atoms, which may be substituted at the nitrogen atom by an alkylsulphonyl or acyl group, wherein, if the acyl group is an alkanoyl group, it may additionally be substituted by an alkoxy group, and the alkyl substituent may be substituted at position 2 by a hydroxy, alkoxy or arylamino group, an N-alkoxycarbonyl-alkylamino, N-cycloalkoxycarbonylalkylamino, N-cycloalkylalkoxycarbonyl-alkylamino, Naryloxycarbonyl-alkylamino or N-aralkoxycarbonylalkylamino group, in which the alkyl group may contain 1 to 6 carbon atoms in each case, an alkoxycarbonylamino, cycloalkoxycarbonylamino, cycloalkylalkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, acylamino or alkylsulphonylamino group substituted at the nitrogen atom by a cycloalkyl, cycloalkylalkyl or aralkyl group, or a phthalimino, homophthalimino, 2-carboxyphenylcarbonylamino, 2-carboxyphenylmethylamino, 2carboxyphenylmethylenecarbonylamino or 2carboxymethylenephenylcarbonylamino group, whilst a carbonyl group in a phthalimino group may be replaced by a methylene group and a methylene group in a homophthal imino 2 -carboxyphenylmethylenecarbonylamino or 2-carboxymethylenephenylcarbonylamino group may be substituted by one or two alkyl groups, and additionally the above-mentioned phenyl nuclei may be mono- or disubstituted by alkyl or alkoxy groups, whilst the substituents may be identical or different, and at the same time they may be partially or wholly hydrogenated, a bicycloalkane-3-carboxylic acid amino or bicycloalkene-3carboxylic acid amino group substituted by a carboxy group in the 2-position, a bicycloalkane-2,3-dicarboxylic acid imino or bicycloalkene-2,3-dicarboxylic acid imino group, wherein the bicycloalkane and bicycloalkene parts each contain 9 or 10 carbon atoms, may be substituted by 1, 2 or 3 methyl groups and an endomethylene group may be replaced by an oxygen atom, a glutaric acid imino or 3carboxy-n-propylene-carbonyl group wherein the npropylene group may be perfluorinated, substituted by one or two alkyl groups or by a tetramethylene or pentamethylene group, and R4 has the meanings mentioned hereionbefore for R,., with the exception of the amino group: Acylation of a compound of the general formula (XIX) (in which R2, R3, Rs and Re are as hereinbefore defined, R4 is as hereinbefore defined, with the exception of the amino group, and R13 denotes a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, which may be substituted at position 2 by a hydroxy, alkoxy or arylamino group, a cycloalkyl, cycloalkylalkyl or aralkyl group) using a compound of the formula R„ —Zs (XX) (in which »14 denotes a dialkylaminoalkanoyl, cycloalkoxycarbonyl, cycloalkylalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl or trifluoroacetyl group, an alkylsulphonyl group having 1 to 4 carbon atoms, an alkoxycarbonyl group having a total of 2 to 7 carbon atoms, a thiazolidin-3-ylcarbonyl group substituted by an alkoxycarbonyl group, or an acyl group, in which, if the acyl group is an alkanoyl group, it may additionally be substituted by an alkoxy group, or a 2-carboxyphenylcarbonyl, 2-carboxyphenylmethyl, 2-carboxyphenyl65 methylenecarbonyl or 2-carboxymethylenephenylcarbony1 group, whilst a methylene group in a 2-carboxyphenylmethylenecarbonyl or 2-carboxymethylenephenylcarbonyl group may be substituted by one or two alkyl groups, and in addition the above-mentioned phenyl nuclei may be mono- or disubstituted by alkyl or alkoxy groups, the substituent being identical or different, and at the same time they may be wholly or partially hydrogenated, a bicycloalkane-3-carbonyl or bicycloalkene-3-carbonyl group substituted in the 2-position by a carboxy group, wherein the bicycloalkane and bicycloalkene moieties each contain 9 or 10 carbon atoms, may be substituted by 1, 2 or 3 methyl groups and an endomethylene group may be replaced by an oxygen atom, a 3-carboxy-n-propylene15 carbonyl group wherein the n-propylene group may be perfluorinated, substituted by one or two alkyl groups or by a tetramethylene or pentamethylene group, and Z3 denotes a nucleophilic leaving group) or reactive derivatives thereof, such as acid halides, acid esters or acid anhydrides.
Suitable examples of reactive derivatives of a compound of the formula XIX are esters thereof, such as methyl, ethyl or benzyl esters; thioesters thereof, such as methylthio or ethylthio esters; halides thereof, such as acid chlorides, anhydrides or imidazolides thereof.
The reaction is advantageously carried out in a solvent or solvent mixture, such as water, methylene chloride, chloroform, ether, tetrahydrofuran, dioxane or dimethylformamide, using a corresponding carboxylic acid in the presence of an acid activating or dehydrating agent, such as thionyl chloride, using anhydrides thereof, such as acetic anhydride, using esters thereof, such as ethyl acetate, using halides thereof, such as acetyl chloride or methanesulphonyl chloride, optionally in the presence of an inorganic or tertiary organic base, such as sodium hydroxide, potassium carbonate, triethylamine or pyridine, wherein the two latter bases may also serve as solvent at the same time, at temperatures between -25 and 100 °C, but preferably at temperatures between -10 and 80 °C. n) In order to prepare compounds of general formula I wherein at least one of the groups Ry or Rz represents a 2 -carboxyphenylcarbonylamino, 2 -carboxyphenylmethylamino, 2- carboxyphenylmethylenecarbonylamino or 2-carboxymethylenephenylcarbonylamino group, where a methylene group in a 2-carboxyphenylmethylenecarbonylamino or 2carboxymethylenephenylcarbonylamino group may be substituted by one or two alkyl groups, and in addition the above-mentioned phenyl nuclei may be mono- or disubstituted by alkyl or alkoxy groups, whilst the substituents may be identical or different, and at the same time may be wholly or partially hydrogenated, a bicycloalkane-3-carboxylic acid amino or bicycloalkene-3carboxylic acid amino group substituted by a carboxy group in the 2-position, wherein the bicycloalkane and bicycloalkene moieties each contain 9 or 10 carbon atoms, may be substituted by 1, 2 or 3 methyl groups and an endomethylene group may be replaced by an oxygen atom, a 3- carboxy-n-propylenecarbonyl group wherein the npropylene group may be perfluorinated, substituted by one or two alkyl groups or by a tetramethylene or pentamethylene group: Partial hydrolysis of a compound of general formula (XXI) wherein R2 to R6 are defined as hereinbefore and R1S represents a phthalimino or homophthalimino group, whilst a carbonyl group in a phthalimino group may be replaced by a methylene group and a methylene group in a homophthalimino group may be substituted by one or two alkyl groups, and in addition the above-mentioned phenyl nuclei may be mono- or disubstituted by alkyl or alkoxy groups, the substituents being identical or different, and at the same time may be wholly or partially hydrogenated, a bicycloalkane-2,3-dicarboxylie acid imino or bicycloalkene-2,3-dicarboxylic acid imino group wherein the bicycloalkane and bicycloalkene moieties each contain 9 or 10 carbon atoms, may be substituted by 1, 2 or 3 methyl groups and an endomethylene group may be replaced by an oxygen atom, a glutaric acid imino group wherein the n-propylene group may be perfluorinated, substituted by one or two alkyl groups or by a tetramethylene or pentamethylene group.
Partial hydrolysis is expediently carried out either in the presence of an acid such as hydrochloric, sulphuric, phosphoric, trichloroacetic or trifluoroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as waiter, water/methanol, ethanol, water/ethanol, water/isopropanol or water/dioxan at temperatures between -10eC and 120’C, e.g. at temperatures between ambient temperature and the boiling temperature of the reaction mixture. However, it is particularly advantageous to carry out the partial hydrolysis in the presence of one equivalent of an inorganic base at ambient temperature.
In the reactions described above, optionally present reactive groups, such as hydroxy, amino or alkylamino groups may be protected during the reaction by conventional protective groups, which are cleaved again after the reaction.
Suitable examples of a protective radical for a hydroxy group are the trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranyl group, and of protective radicals for an amino, alkylamino or imino group are acetyl, benzoyl, ethoxycarbonyl or benzyl groups.
The optional subsequent cleaving of a protective group used is preferably carried out hydrolytically in an aqueous solvent, for example in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid, such as hydrochloric acid or sulphuric acid, or in the presence of an alkali metal base, such as sodium hydroxide or potassium hydroxide, at temperatures between 0 and 100 °C, preferably at the boiling temperature of the reaction mixture. However, cleaving a benzyl radical is preferably carried out hydrogenolyti20 cally, for example with hydrogen in the presence of a catalyst, such as palladium/carbon, in a solvent, such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with addition of an acid, such as hydrochloric acid, at temperatures between 0 and 50 °C, but preferably at ambient temperature, and a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar.
If a compound of the formula I in which Rx and/or R2 is a nitro group is obtained in accordance with the invention, it may be converted to a corresponding amino compound of the formula I by means of reduction, or if a compound of the formula I in which Rx and/or Rj is a hydroxy, amino, alkylamino, phenylalkylamino, alkylsulphonylamino or acylamino group is obtained in accordance with the invention, it may be converted to a corresponding alkylated compound of the formula I by means of alkylation, or if a compound of the formula I in which Rx and/or R2 is a benzyloxy group is obtained in accordance with the invention, it may be converted to a corresponding compound of the formula I, in which Rx and/or R2 is a hydroxy group, by means of debenzylation, or if a compound of the formula I in which Rx and/or R2 is a IO carboxy group is obtained in accordance with the invention, it may be converted to a corresponding compound of the formula I, in which Rx and/or R2 is an aminocarbonyl group optionally substituted by one or two alkyl groups each having 1 to 3 carbon atoms, by means of amidation, or if a compound of the formula I in which Rx and/or Rz is a carboxy group and/or R* is a cyano group is obtained in accordance with the invention, it may be converted to a 2q corresponding compound of the formula I, in which Rx and/or R2 is a hydroxymethyl group and/or R« is an aminomethyl group , by means of reduction, or if a compound of the formula I in which Rx and/or R2 is an alkoxycarbonyl group is obtained in accordance with the invention, it may be converted in accordance with the invention to a corresponding compound of the formula I, in which Rx and/or R2 is a carboxy group, by means of hydrolysis, or if a compound of the formula I in which Rx and/or R2 is an alkoxy or phenylalkoxy group is obtained in accordance with the invention, it may be converted to a corresponding compound of the formula I, in which Rx and/or R2 is a hydroxy group, by means of ether cleaving, or if a compound of the formula I, in which Rx and/or R2 is an aminocarbonylamino or aminothiocarbonyl group, which is substituted by a cycloalkyl group having 5 to 10 carbon atoms, in which a methylene group is replaced in the 2 position by an oxygen atom, and which may be additionally monosubstituted or disubstituted by an alkyl group having 1 to 20 carbon atoms, by an alkenyl or alkynyl group each having 3 to 5 carbon atoms, by a bicyclic or tricyclic alkyl group having 7 to 11 carbon atoms, by a cycloalkyl, cycloalkylalkyl, aralkyl or aryl group, is obtained in accordance with the invention, it may be converted to a corresponding compound of the formula I, in which Rx and/or R2 is an aminocarbonylamino or aminothiocarbonyl group, which is substituted by a 4hydroxy-n-butyl, 5-hydroxy-n-pentyl or 6-hydroxy-n-hexyl group and may additionally be monosubstituted or disubstituted by an alkyl group having l to 20 carbon atoms, by an alkenyl or alkynyl group each having 3 to 5 carbon atoms, by a bicyclic or tricyclic alkyl group having 7 to 11 carbon atoms, by a cycloalkyl, cycloalkylalkyl, aralkyl or aryl group, by means of reduction, or if a compound of the formula I, in which Rx and/or is a phthalimino group, which may be monosubstituted or disubstituted by an alkyl or alkoxy group, wherein the substituents may be the same or different, is obtained in accordance with the invention, it may be converted to a corresponding compound of the formula I, in which Rx and/or R2 is a l-oxo-isoihdolin-2-yl group, which may be monosubstituted or disubstituted by an alkyl or alkoxy group, wherein the substituents may be the same or different, by means of reduction, or a resulting 1 and 3 isomer mixture of a compound of the formula I may be separated into its 1 isomer and 3 isomer by means of isomer separation.
The subsequent reduction of the nitro group is preferably carried out in a solvent, such as water, water/ethanol, methanol, glacial acetic acid, ethyl acetate or dimethylformamide, advantageously using hydrogen in the presence of a hydrogenation catalyst, such as Raney nickel, platinum or palladium/carbon, using metals, such as iron, tin or zinc, in the presence of an acid, using salts, such as iron (II) sulphate, tin (II) chloride, ]0 sodium sulphide, sodium hydrogen sulphite or sodium dithionite, or using hydrazine in the presence of Raney nickel, at temperatures between 0 and 80 °C, but preferably at temperatures between 20 and 40 °C.
The subsequent alkylation is preferably carried out in a solvent or solvent mixture, such as methylformamide, dimethyl formamide, dimethylsulphoxide, benzene, chlorobenzene, tetrahydrofuran, benzene/tetrahydro furan or dioxane, in the presence of an alkylating agent, such 2q as methyl iodide, methylbromide, ethylbromide, dimethylsulphate, benzylchloride or diazomethane, optionally preferably in the presence of an acid-binding agent, for example an alkoxide such as potassium tert.butoxide, an alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide, an alkali metal carbonate, such as potassium carbonate, an alkali metal amide, such as sodium amide, or an alkali metal hydride, such as sodium hydride, advantageously at temperatures between 0 and 150 °C, preferably at temperatures between 0 and 50 °C.
The subsequent reductive amination of an amino group is carried out in a suitable solvent, such as methanol, ethanol, tetrahydrofuran, dioxane or acetonitrile, in the presence of a suitable reducing agent, such as a suitable complex metal hydride, but preferably in the presence of sodium cyanoborohydride, at a pH of 5 to 7, at temperatures between 0 and 50 °C, but preferably at ambient temperature.
The subsequent cleaving of a benzyl radical is preferably 5 carried out hydrogenolytically, for example using hydrogen in the presence of a catalyst, such as palladium/carbon, in a solvent, such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with addition of an acid, such as hydrochloric acid, at temperatures between 0 and 50 °C, but preferably at ambient temperature, and a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar.
The subsequent amidation is advantageously carried out in a solvent, such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, but particularly advantageously in an excess of the amine used, for example in methanol, ethanol, n-propanol, 2Q isopropanol, ammonia, methylamine, ethylamine, dimethylamine or diethylamine, optionally in the presence of an acid activating agent or a dehydrating agent, for example in the presence of ethyl chloroformate, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N, N' -dicyclohexylcarbodiimide, N, N · -dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,Ν'-carbonyldiimidazole or Ν,Ν'-thionyldiimidazole or triphehylphosphine/carbon tetrachloride, or an agent activating the amino group, for example phosphorus trichloride, and optionally in the 3q presence of an inorganic base, such as sodium carbonate, or a tertiary organic base, such as triethylamine or pyridine, which may serve as solvent at the same time, at temperatures between -25 °C and 250 °C, but preferably at temperatures between -10 °C and the boiling temperature of the solvent used.
The subsequent reduction of the carboxy group is carried out in a suitable solvent, such as methanol, ethanol, -73ether, tetrahydrofuran, dioxane or glacial acetic acid, in the presence of catalytically activated hydrogen, for example hydrogen in the presence of platinum or palladium/carbon, and optionally in the presence of an acid, such as hydrochloric acid or perchloric acid, or in the presence of a metal hydride, such as sodium borohydride, lithium borohydride or lithium aluminium hydride, at temperatures between 0 and 100 °C, preferably at temperatures between 20 and 80 °C.
The subsequent hydrolysis is preferably carried out hydrolytically in an aqueous solvent, for example in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid, such as hydrochloric acid or sulphuric acid, or in the presence of an alkali metal base, such as sodium hydroxide or potassium hydroxide, at temperatures between 0 and 100 °C, preferably at the boiling temperature of the reaction mixture.
The subsequent ether cleaving is carried out in the presence of an acid, such as hydrogen chloride, hydrogen bromide, sulphuric acid, boron trichloride, boron tribromide or aluminium chloride, in a suitable solvent, such as methanol, ethanol, water/isopropanol, methylene chloride, chloroform or carbon tetrachloride, at temperatures between -30 °C and the boiling temperature of the reaction mixture.
The subsequent reduction is preferably carried out in a solvent, such as water, water/ethanol, methanol, glacial acetic acid, ethyl acetate or dimethylformamide, advantageously using hydrogen in the presence of a hydrogenation catalyst, such as Raney nickel, platinum or palladium/carbon, or using hydrazine in the presence of Raney nickel, at temperatures between 0 and 50 °C, but preferably at ambient temperature.
The subsequent reduction of a phthalimino group is preferably carried out in a solvent, such as glacial acetic acid using nascent hydrogen, for example using zinc/glacial acetic acid, at temperatures between 80 and 120 °C, preferably at the boiling temperature of the reaction mixture.
The subsequent isomer separation is preferably carried out chromatographically using a carrier, such as silica gel or aluminium oxide.
Furthermore, the compounds of the formula I obtained may be converted to their acid addition salts, in particular for the pharmaceutical application, to their physiologicallyacceptable salts, using inorganic or organic acids. Examples of acids suitable for this purpose are hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. in addition, the novel compounds of the formula I thus obtained, if they contain a carboxy group, can then be converted, if desired to their addition salts using inorganic or organic bases, in particular for the pharmaceutical application, to their physiologically acceptable addition salts. Examples of bases suitable for this purpose are sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
Some of the compounds of the formulae II to XXI used as starting materials are known in the literature or they are obtained by processes known in the literature.
Thus for example a compound of the formula II or III is obtained by alkylating a corresponding o-amino-nitro compound and subsequently reducing the nitro group.
A compound of the formulae V, VI, VII, IX, X, XI, XIII, XV, XVII, XIX or XXI used as starting material is obtained by alkylating a corresponding o-phenylenediamine or a corresponding o-amino-nitro compound and subsequently reducing the nitro group and subsequently cyclising an o-diaminophenyl compound thus obtained, or by NH-alkylating a corresponding lH-benzimidazole, wherein the isomer mixture thus obtained may then be separated by means of conventional methods, for example by means of chromatography.
The novel compounds of the formula I and their physiologically acceptable addition salts have valuable pharmacological properties. In particular, they are angiotensin II antagonists.
By way of example, the compounds A = 4 · - [ (2-n-butyl-benzimidazol-l-yl)-methyl]biphenyl-2carboxylic acid, B = 4’-[(2—methoxymethyl—benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid, C — 4·—[(2—methyl—5—and 6-butanoylamino-benzimidazol-lyl)-methyl]biphenyl-2-carboxylxc acid, D = 4·—[(2-n-propyl-benzimidazol-l-yl)-methyl]biphenyl-2carboxylic acid, E = 4’—((2-ethyl-benzimidazol-l-yl)-methyl]biphenyl-2carboxylic acid, F = 4'-[(2-methylthiomethyl-benz imidazol-l-yl)-methyl]76 biphenyl-2-carboxylic acid semi-trifluoroacetate, G = 4 * - [(2-ethylthio-benzimidazol-l-yl)-methyl]biphenyl2-carboxylic acid, H = 4'-[(2-n-butyl-5-methoxy-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid, 1 - 4‘-[(2-n-butyl-6-methoxy-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid, j s= 4 · — [ (2-n-butyl-5,6-dimethyl-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid, K = 4·—[(2—n-propyl—naphtho[2,3—d]imidazol—1—yl)— methyl]biphenyl-2-carboxylic acid, L = 4’—[(2—n-butyl—5,6—dimethoxy—benzimidazol—1—yl)— methyl)biphenyl-2-carboxylic acid, M = 4’—[(2—(1—butyn—4—yl)—benzimidazol—1—yl]—methyl]— biphenyl-2-carboxylic acid, N =. 4’-[(2-n-butyl-5-acetyl-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid, O = 4’-[(2-cyclohexylmethyl-5,6-dihydroxy-benzimidazol-ly1)-methyl]biphenyl-2-carboxylic acid, P = 4'-[(6-aminothiocarbonylamino-2-n-butyl-benzimidazol1-yl)-methyl]biphenyl-2-carboxylic acid hemihydrate, Q = 4·-[(6-aminocarbonylamino-2-n-butyl-benzimidazol-lyl)-methyl]biphenyl-2-carboxylic acid trifluoroacetate and R = 4'—[(2-n-butyl-5-(n-butylaminocarbonylamino)77 benzimidazol-l-yl)-methyl]biphenyl-2-carboxy1ic acid semi-trifluoroacetate were investigated for their biological effects as 5 follows: a) rats (male, 180-220 g) are anaesthetised using sodium hexobarbital (150 mg/kg i.p.). After the anaesthetic has taken effect, a tracheal cannula is inserted, the spine is destroyed in the animals and then they are immediately respirated artifically using a respiratory pump. The arterial blood pressure is recorded via a cannula in the carotid artery by means of a Bell & Howell pressure sensor. Substances are administered via a cannula in the jugular vein.
Test substances are administered in three doses (10, 20 and 30 mg/kg i.v.), wherein one dose of substance is tested per animal. Three minutes after intravenous administration of the test substance, angiotensin II is administered intravenously in increasing doses, and hence a cumulative dose-effect relationship is established for angiotensin II in the presence of the test substances.
The measured parameter is the increase in the arterial blood pressure.
These dose-effect graphs are compared with standard graphs for angiotensin II without test substances. A computer program determines the displacements to the right of the dose-effect graphs for angiotensin II as a result of test substances, and calculates corresponding pA2 values for the test substances.
The following table shows the average pA2 values of the substances investigated: Substances pAz values A 4.40 B 5.10 C 5.30 D 5.49 E 5.25 F 5.25 G 5.10 H 5.00 I 5.17 J 5.41 K 4.90 L 5.27 M 4.97 N 4.88 O - P 5.22 Q 5.43 R 5.47 b) The inhibiting effect of the novel compounds on the bonding of angiotensin II to bovine adrenal gland receptor preparations was tested analogously to the method of Glossmann et al.(J. Biol. Chem. 249. 825-834 (1974). The incubation batch contained aliquots of a membrane preparation of bovine adrenal cortex in tris buffer, increasing concentrations of the possible antagonists and 50 pM u5I-angiotensin II. After 45 minutes the incubation was stopped by rapid filtration through glass fibre filters. The radioactivity associated with the filter was determined in a 7-counter at a counting efficiency of 80 %.
The following table shows the inhibitor concentration of the antagonists which effected 50 % inhibition of the specific "5I-angiotensin II bonding: Substances IC50 [μΜ/1] 15 A 1.2 B 5.9 C 1.9 D 0.6 E 1.0 20 ' F 1.5 G 2.1 H 0.9 I 2.4 J 9.5 25 K 2.3 L 4.0 M 6.4 N 2.4 O 29.0 30 P 0.8 Q 0.9 R 1.0 Furthermore, no toxic side effects could be observed for the administration of the above compounds up to a dose of mg/kg i.v., for example no negative inotropic effect and no cardiac rythmn disorders. Accordingly, the compounds are well tolerated.
In view of their pharmacological properties, the new compounds of formula I wherein R4 is a group containing a Bronsted acid or a group which may be converted in vivo into a Bronsted acid, and their physiologically acceptable addition salts, are suitable for the treatment of hypertonia and cardiac insufficiency, also for the treatment of ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), for preventing the progression of cardiac insufficiency after myocardial infarction, for the treatment of diabetic nephropathy, glaucoma, gastrointestinal illnesses and diseases of the bladder.
The dosage required to achieve a corresponding effect is conveniently 20 to 100 mg for intravenous administration, preferably 30 to 70 mg, and 50 to 200 mg for oral administration, preferably 75 to 150 mg, 1 to 3 x daily in each case. The compounds of the formula I in which R4 denotes a group containing a Bronsted acid or a group which may be converted in vivo into a group containing a Bronsted acid prepared in accordance with the invention can be formulated for this purpose, optionally in combination with other active ingredients, together with one or more inert conventional excipients and/or diluents, for example with com starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose orfat-containing substances, such as hard fat or suitable mixtures thereof, in conventional galenic preparations, such as tablets, coated tablets, capsules, powders, suspensions or suppositories.
The following Examples should illustrate the invention in more detail: Example A Tert.butyl 4·-[N-(5-benzylamino-2-nitrophenyl) pentanoylaminomethyl ] biphenyl-2-carboxylate 3.9 g (7.5 mmol) of tert.butyl 4'-[N-(5-chloro-2-nitrophenyl) -pentanoylaminomethyl ] biphenyl-2-carboxylate are stirred together with 3.9 ml of benzylamine for 3 hours in an oil bath heated at 150-160 °C. After cooling the reaction mixture, the residue is dissolved in about 25 ml of methylene chloride and the substance is purified over a silica gel column (grain size: 0.063-0.2 mm, eluting agent: cyclohexane/5-10 % ethyl acetate). The appropriate fractions are evaporated on a rotary evaporator.
Yield: 2.9 g (65,.5 % of theoretical), Oil, Rf value: 0.55 (Silica gel: cyclohexane/ethyl acetate = 2:1) The following compounds are obtained in analogous manner: tert. butyl 4 · - [N- (5- (N-benzyl-methylamino) -2-nitrophenyl ) -pentanoylaminomethyl ] biphenyl-2-carboxylate oil, Re value: 0.40 (Silica gel: cyclohexane/ethyl acetate = 4:1) tert.butyl 4'-[N-(5-dimethylamino-2-nitrophenyl)pentanoylaminomethyl ] biphenyl-2-carboxylate oil, Rc value: 0.35 (Silica gel: hexane/ethyl acetate = 4:1) Example 1 Tert-butyl 4’-((benzimidazol-l-yl)-methyl]biphenyl-2carboxylate 0.95 g (8 mmol) of benzimidazole are dissolved in 50 ml of dimethylsulphoxide and treated with 1.0 g (9 mmol) of potassium tert.butoxide. To form the salt, the mixture is then stirred for 30 minutes at ambient temperature and 2.8 g (8 mmol) of tert.butyl 4*-bromomethyl-biphenyl-2carboxy-late are then added. The reaction is completed after stirring for 2 hours at ambient temperature. The mixture is diluted to 500 ml using water and extracted 3 times using about 100 ml of ethyl acetate. The combined organic phases are dried using magnesium sulphate and evaporated to dryness. The oily residue is purified over a silica gel column (grain size: 0.063-0.2 mm), methylene chloride with 1 % ethanol being used as eluting agent.
The homogeneous fractions are evaporated to dryness. The residue is an oil.
Yield: 2.8 g (90.8 % of theoretical), Rf value: 0.35 (Silica gel: methylene chloride/ethanol = 19:1) Calculated: C 78.10 H 6.29 N 7.29 Found: 78.18 6.34 7.19 The following compounds are obtained in analogous manner: tert.butyl 4’-[(2-hydroxy-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.15 (Silica gel:methylene chloride/ethanol = 49:1) tert.butyl 4 *-[(2-n-butyl-7-(2-diethylamino-ethoxy)-4methyl-benzimidazol-l-yl) -methyl]biphenyl-2-carboxylate oil, Rc value: 0.55 (Silica gel: methylene chloride/ethanol = 9:1) tert.butyl 4'-[(2-ethylthio-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.45 (Silica gel: methylene chloride/ethanol = 49:1) tert.butyl 4(2-n-propylthiomethyl-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate oil, R£ value: 0.55 (Silica gel: methylene chloride/ ethanol = 19:1) tert.butyl 4^-((2-methyl-benzimidazol-l-yl)-methyl]biphenyl-2-carboxy1ate oil, Rf value: 0.60 (Silica gel: methylene chloride/ethanol = 19:1) tert.butyl 4’-[(2-methylmercapto-benzimidazol-l-yl)methyl)biphenyl-2-carboxylate oil, Rf value: 0.55 (Silica gel: methylene chloride/ethanol = 19:1) tert.butyl 4·-[(2-methyl-5-and 6-nitro-benzimidazol-lyl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.50 (Silica gel: methylene chloride/ethanol = 19:1) tert.butyl 4*-[(2-methyl-5-and 6-butanoylaminobenz imidazol-l-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.60 (Silica gel: methylene chloride/ethanol = 9:1) tert.butyl 4’-[(2-(2-methylpropyl)-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate oil, Rf value: 0.50 (Silica gel: methylethylketone/xylene = 1.1) tert.butyl 4’-[(2-methoxymethyl-benzimidazol-l-yl)methyl)biphenyl-2-carboxylate oil, Rf value: 0.50 (Silica gel: methylethylketone/xylene = 1:1) tert.butyl 4'-[(2-(pyrid-2-yl)-benzimidazol-l-yl) methyl]biphenyl-2-carboxylate oil, Rf value: 0.40 (Silica gel: methylene chloride/ethanol = 19:1) tert.butyl 4 * -[(5-and 6-methy1-benzimidazol-1-yl)methyl]biphenyl-2-carboxylate oil, Rf value: 0.25 (Silica gel: methylene chloride/ethanol = 19:1) tert.butyl 4 ’-[ (2-phenyl-benzimidazol-l-yl) -methyl]biphenyl-2-carboxy1ate oil, Rf value: 0.45 (Silica gel: methylene chioride/ethanol = 19:1) tert.butyl 4’-[(2-(thiazol-4-yl)-benzimidazol-l-yl)methyl ]biphenyl-2-carboxylate oil, Rf value: 0.30 (Silica gel: methylene chloride/ethanol » 49:1) tert.butyl 4'-[ (2-(3,5?-dimethyl-pyrazol-l-yl)-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.35 (Silica gel: methylene chloride/ethanol =19:1) tert.butyl 4·-[(2-(fur-2-yl)-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.40 (Silica gel: methylene chioride/ethanol « 19:1) tert.butyl 4 · -[ (2-aminocarbonylamino-benzimidazol-l-yl)methyl ] biphenyl-2 -carboxylate oil, Rf value: 0.50 (Silica gel: methylene chloride/ethanol = 19:1) tert.butyl 4 ·-[(2-isopropyl-benzimidazol-l-yl)-methyl]b ipheny1-2-carboxylate oil, Rf value: 0.50 (Silica gel: methylethylketone/xylene = 1:1) tert.butyl 4·-[(2-hydroxymethyl-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate oil, Rf value: 0.35 (Silica gel: methylene chloride/ethanol = 19:1) tert.butyl 4(2-(3-hydroxypropyl)-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate oil, R£ value: 0.40 (Silica gel: methylene chloride/ ethanol = 19:1) tert.butyl 4'-[(2-methyl-5-and 6-(N-(methoxyacetyl)-nbutylamino)-benzimidazol-l-yl)-methyl]biphenyl-2carboxylate oil, Rf Value: 0.20 (Silica gel: methylene chloride/ ethanol = 19:1) tert.butyl 4'-[(2-(1-methylpropyl)-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate oil, Rf value: 0.80 (Silica gel: methylethylketone/xylene = l:l) tert.butyl 4'-[(2-(2-methylbutyl)-benzimidazol-l-yl) methyl]biphenyl-2-carboxylate oil, Rf value: 0.60 (Silica gel: methylethylketone/xylene = 1:1) tert.butyl 4'-[(2-methyl-5-and 6-(N—(2-methoxyethyl)-nbutylamino)-benzimidazol-l-yl)-methyl]biphenyl-2carboxylate oil, Rf value: 0.25 (Silica gel: methylene chloride/ethanol = 19:1) tert.butyl 4’-((2-n-pentyl-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate oil, R£ value: 0.50 (Silica gel: methylethylketone/xylene = 1:1) tert.butyl 4·-[(2-n-butyl-7-methoxy-4-methylbenzimidazol-l-yl) -methyl ]biphenyl-2-carboxylate oil, Rf value: 0.50 (Silica gel: methylene chloride/ethanol — 19:1) tert.butyl 4·-[(2-n-propyl-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate melting point: 140-14Γ °C tert.butyl 4’-[(2-ethyl-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate melting point: 129-130 °C tert.butyl 41-[(2-ethylthiomethyl-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate oil, Rf value: 0.50 (Silica gel: methylene chloride/ethanol » 19:1) tert.butyl 4' -[ (2-methylthiomethyl-benzimidazol-l-yl) methyl]biphenyl-2-carboxylate oil, Rf value: 0.45 (Silica gel: methylene chloride/ethanol = 19:1) tert.butyl 4'-[(2-chloro-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.55 (Silica gel: methylene chloride/ethanol = 19:1) tert.butyl 4·-[(2-n-butylthio-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate oil, Rf value: 0.55 (Silica gel: methylene chloride/ethanol = 49:1) tert.butyl 4'—[(2-(4-methoxyphenyl)-benzimidazol-l-yl)methyl)biphenyl-2-carboxylate oil, Rf value: 0.80 (Silica gel: methylethylketone/xylene = 1:1) tert.butyl 4·-[(2-n-propylthio-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate oil, Rf value: 0.50 (Silica gel: methylene chloride/ethanol = 49:1) tert.butyl 41-[(2-n-butylamino-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate oil, Rf value: 0.45 (Silica gel: methylene chloride/ethanol = 19:1) tert.butyl 41-[(2-(4-methoxyphenyl)-5-and 6-chlorobenzimidazol-l-yl)-methyl ] biphenyl-2-carboxylate oil, Rf value: 0.50 (Silica gel: methylethylketone/xylene = 1:1) tert.butyl 4'-[(2-n-butyl-5-and 6-acetaminobenzimidazol-l-yl)-methyl ] biphenyl-2-carboxylate oil, Rf value: 0.60 (Silica gel: ethyl acetate/ethanol/ammonia = 90:10:1) tert.butyl 4’-[(2-n-butyl-5-and 6-butanoylaminobenzimidazol-l-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.80 (Silica gel: ethyl acetate/ethanol/ammonia = 90:10:1) tert.butyl 41 - [ (2-n-butyl-5-and 6-methoxy-benzimid-azol1-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.70 (Silica gel: methylethylketone/xylene = 1:1) tert.butyl 4'-[(7-n-butoxy-2-n-butyl-4-methylbenziraidazol-l-yl) -methyl] biphenyl-2-carboxylate oil, Rf value: 0.55 (Silica gel: methylene chloride/ethanol = 19:1) tert.butyl 4' -[ (2- (4-hydroxyphenyl) -benzimidazol-l-yl) methyl]biphenyl-2-carboxylate melting point: 258-260 °C tert.butyl 4'-[(2-(4-n-butoxyphenyl)-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate oil, Rf value: 0.70 (Silica gel: methylethylketone/xylene = 1:1) tert.butyl 4'-[(2-n-butyl-4-nitro-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate oil, Rf value: 0.45 (Silica gel: methylene chloride/ethanol = 19:1) z’ tert.butyl 4 · - [ (2 - (3-pyridyl)-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate oil, Rf value: 0.40 (Silica gel: methylethylketone/xylene = 5:2) tert.butyl 4 · -[ (2-(4-benzyloxyphenyl)-benzimidazol-lyl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.75 (Silica gel: methylethylketone/xylene = 1:1) tert.butyl 4’-((2-n-butyl-5,6-dimethyl-benzimidazol-lyl )-methyl]biphenyl-2-carboxylate oil, Rf value: 0.50 (Silica gel: methylene chloride/ethanol = 19:1) tert.butyl 4'-((2-(2,2-dimethylpropyl)-5,6-dimethylbenz imidazol-l-yl) -methyl ] bipheny1-2-carboxylate oil, Rf value: 0.48 (Silica gel: methylene chloride/ethanol = 19:1) tert.butyl 4'—[(2-benzyl-5,6-dimethyl-benzimidazol-lyl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.52 (Silica gel: methylene chloride/ethanol = 19:1) tert.butyl 4’-[(2-(2-methylbutyl)-5,6-dimethyl-benzimid azol-l-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.50 (Silica gel: methylene chloride/ethanol = 19:1) tert.butyl 41-[(2-cyclohexylmethy1-5,6-dimethylbenzimidazol-l-yl) -methyl ] biphenyl - 2 -carboxylate oil·; Rf value: 0.52 (Silica gel: methylene chloride/ethanol = 19:1) tert.butyl 4'-[(2-cyclohexylmethyl-5,6-dichlorobenz imidazol-l-yl) -methyl ] biphenyl-2-carboxylate oil, Rf value: 0.46 (Silica gel: methylene chloride/ethanol = 19:1) tert.butyl 4'-[(2-(2-methylbutyl)-naphtho[2,3-d]imidazol-l-yl) -methyl ] bipheriyl-2-carboxylate oil, Rf value: 0.57 (Silica gel: methylene chloride/ethanol = 19:1) tert.butyl 41-[(2-n-propyl-naphtho[2,3-d]imidazol-l-yl) methyl)biphenyl-2-carboxylate oil, Rf value: 0.57 (Silica gel: methylene chloride/ethanol = 19:1) tert.butyl 4'-[(2-n-butyl-5,6-dichloro-benzimidazol-lyl )-methyl]biphenyl-2-carboxylate oil, Rf value: 0.45 (Silica gel: methylene chloride/ethanol = 19:1) tert. butyl 4 1 - [ (2-cyclohexylmethyl-5,6-dimethoxy— benz imidazol-l-yl) -methyl ]biphenyl-2-carboxylate oil, Rc value: 0.47 (Silica gel: methylene chioride/ethanol = 19:1) tert. butyl 4 ’ - [ (2-n-butyl-5,6-dimethoxy-benzimidazol-lyl)-methyl]biphenyl-2-carboxylate oil, R£ value: 0.46 (Silica gel: methylene chloride/ethanol = 19:1) tert. butyl 4 · - [ (2-cyclopentylmethy 1-5,6-dimethoxybenzimidazol-l-yl) -methyl ]biphenyl-2-carboxylate oil, Rf value: 0.47 (Silica gel: methylene chloride/ethanol - 19:1) tert. butyl 4/((2-(3 -methylbutyl )-5,6-dimethoxybenz imidazol-l-yl) -methyl ] biphenyl-2-carboxylate oil, Re value: 0.47 (Silica gel: methylene chloride/ethanol, ώ 19 :1) tert. butyl 41 - [ (2-cyclohexyl-5,6-dimethyl-benzimidazoll-yl)-methyl ]biphenyl-2-carboxylate oil, Rf value: 0.50 (Silica gel: methylene chloride/ethanol = 19:1) tert .butyl 4' -[ (2- (l-butyn-4-yl) -benz imidazol-l-yl) methyl]biphenyl-2-carboxylate oil, Rf value: 0.49 (Silica gel: methylene j0 chloride/ethanol = 19:1) tert.butyl 41-[(2-n-butyl-6-ethoxycarbonyl-benzimidazol 1-y1)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.60 (Silica gel: petroleum ether/ethyl .,- acetate = 1:1 + 1 % glacial acetic acid) tert. butyl 4 · - ( (2 -cyclopentyl-5,6-dimethy1-benz imidazol 1-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.50 (Silica gel: methylene chloride/ethanol = 19:1) tert.butyl 4’-[(2-n-butyl-5-and 6-fluoro-benzimidazol-lyl)-methyl]biphenyl-2-carboxylate oil, R£ value: 0.25 (Silica gel: methylene chloride/ethanol = 50:1) tert.butyl 4'-((2-n-butyl-5-and 6-benzoy1-benzimidazoll-yl) -methyl)biphenyl-2-carboxylate oil, Rf value: 0.28 (Silica gel: methylene chloride/ethanol = 50:1) tert.butyl 4 '-[ (2-n-butyl-5-and 6-trifliioromethylbenzimidazol-l-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.33 (Silica gel: methylene chloride/ethanol = 50:1) tert.butyl 4’-[(2-n-butyl-4-cyano-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate oil, Rf_value: 0.50 (Silica gel: methylene chloride/ethanol = 19:1) tert.butyl 4 *-[ (2-n-butyl-5-arid 6-n-butylaminocar-bonylbenzimidazol-l-yl)-methyl]biphenyl-2-carboxylate oil, Rf value:0.30(Silicagel:methylene chloride/methanol/ acetic acid = 19:0.8:0.2) tert.butyl 4’-[(2-n-butyl-6-carboxy-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate oil, Rf value: 0.90 (Silica gel: methylene chloride/methanol/acetic acid = 9:0.8:0.2) tert.butyl 4'-[(2-n-butyl-5-carboxy-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate melting point: 224-225 °C tert.butyl 4'-[(2-n-buty1-6-aminocarbonyl-benzimidazoll-yl )-methyl]biphenyl-2-carboxylate melting point: 159-160 °C tert.butyl 4' -[(2-n-butyl-5-aminocarbonyl-benzimidazol1-yl)-methyl]biphenyl-2-carboxylate melting point: 135-138 °C (decomposition) tert.butyl 4'-[(2-n-butyl-5-and 6-cyano-benzimidazol-lyl) -methyl]biphenyl-2-carboxylate oil, R£ value: 0.50 (Silica gel: methylene chloride/ethanol - 100:1) tert.butyl 4 · -[(2-n-butyl-6-(lH-tetrazol-5-yl)-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate melting point: from 115 °C (decomposition) tert.butyl 4'-((2-n-butyl-5-and 6-(lH-tetrazol-5-yl)benz imidazol-1-ylj -methyl ] biphenyl-2 -carboxy late melting point: from 92 °C (decomposition) 41 — [ (2-n-buty1-6-(cis-hexahydrophthalimino)benz imidazol-l-yl) -methyl ]-l-cyano-2-phenylnaphthalene tert.butyl 4'-((2-n-butyl-6-(cis-hexahydrophthalimino)benz imidazol-1-yl) -methyl] -2-phenylnaphthalene-lcarboxylate Example 2 Tert ..butyl 4' - [ (2-n-butyl-5-and 6-nitro-benzimidazol-lyl )-methyl]biphenyl-2-carboxylate a) 2-n-butvl-6-nitro-benzimidazole 11.5 g (0.075 mol) of 4-nitro-o-phenylenediamine are introduced in portions at ambient temperature into a mixture of 8.66 g (0.085 mol) of valeric acid and 120 ml of phosphorus oxychloride. The mixture is then heated for 3 hours under reflux. The reaction mixture is separated in 1.5 kg of iced water, rendered alkaline using concentrated ammonia and extracted three times using 500 ml of ethyl acetate. The organic phase is separated off, dried using magnesium sulphate and rotary evaporated. The oily residue is purified over a silica gel column (grain size: 0.063-0.2 mm, eluting agent: methylene chloride/0-2 % ethanol). The homogeneous fractions are evaporated to dryness.
Yield: 10.2 g (62.2 % of theoretical), Melting point: 139-141 °C Calculated: C 60.27 Found: 60.30 H 5.98 6.00 N 19.17 19.42 b) 9.5 g (43 mmol) of 2-n-butyl-6-nitro-benzimidazole are dissolved in 100 ml of dimethylsulphoxide and treated with 5.3 g (47.6 mmol) of potassium tert.butoxide. The mixture is stirred for 30 minutes and 16.6 g (47.6 mmol) of tert.butyl 4'-bromomethylbiphenyl-2-carboxylate are added. After 2 hours, about 600 ml of water are added to the reaction mixture and it is extracted 3 times using about 200 ml of ethyl acetate. The organic phase is dried using magnesium sulphate and rotary evaporated. The crude product thus obtained is purified over a silica gel column (grain size: 0.063-0.2 mm, eluting agent: methylene chloride/01 % ethanol) . The homogeneous fractions are evaporated to dryness.
Yield: 19.9 g (95.2 % of theoretical), Oil, Rf value: 0.50 (Silica gel: methylene chloride + 5 % ethanol) Calculated: C 71.73 H 6.43 N 8.65 Found: 72.00 6.66 8.80 The following compounds are obtained in analogous 5 manner: tert.butyl 4'-[(2-n-butyl-4-and 7-nitro-benzimid-azol-lyl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.45 and 0.47 (Silica gel: methylene 10 chloride/ethanol = 19:1) tert.butyl 4·-[(2-n-butyl-5-and 6-methoxy-benzimid-azol1-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.55 (Silica gel: methylethylketone/xylene 15 = 1:1) tert.butyl 41-[(2-n-butyl-5-and 6-nitro-benzimidazol-lyl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.60 (Silica gel: methylethylketone/xylene 20 = tert.butyl 41-[(2-n~butyl-5-and 6-chloro-benzimidazol-lyl)-methyl ] biphenyl-2-carboxylate oil, Rf value: 0.55 (Silica gel; methylethylketone/xylene 25 = 1:1) tert.butyl 4’-[(2-n-butyl-5-and 6-acetaminobenzimidazol-l-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.20 (Silica gel: methylethylketone/xylene = 1:1) tert.butyl 4'-[(2-n-butyl-5-and 6-butanoylaminobenzimidazol-l-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.80 (Silica gel: ethyl acetate/ethanol/ ammonia = 90:10:1) Example 3 Tert.butyl 4’-[(5-and 6-amino-2-n-butyl-benzimidazol-lyl )-methyl]biphenyl-2-carboxylate 18.3 g (37.7 mmol) of tert.butyl 4’-[(5-and 6-nitro-2-nbutyl-benz imidazol-l-yl) -methyl) biphenyl-2-carboxylate are dissolved in 200 ml of ethanol, 10 g of Raney nickel are added, and the mixture is hydrogenated for 3 hours at 50 °C and 5 bar hydrogen pressure. When the uptake of hydrogen is completed, the catalyst is filtered off under suction and the filtrate is rotary evaporated. Yield: 17.1 g (100 % of theoretical), Oil, R£ value:0.1 and 0.2 (Silica gel: methylene chloride/ethanol = 95:5) The following compound is prepared in analogous manner: tert.butyl 4*-[(4-and 7-amino-2-n-butyl-benzimidazol-lyl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.20 and 0.22 (Silica gel: methylene chloride/ethanol = 50:1) Example 4 Tert. butyl 4 ’ - [ (6-amino-2-n-butyl-benzimidazol-l-yl) methyl]biphenyl-2-carboxylate (I) and tert.butyl 4·-[ (5-amino-2-n-butyl-benzimidazol-1yl)-methyl]biphenyl-2-carboxylate (II) The isomer mixture of I and II (17.1 g) obtained in Example 3 is separated over a chromatography column filled with 1,700 ml of silica gel (grain size: 0.0630.2 mm), I being initially removed by elution using methylene chloride/ethanol = 98:2.
Yield: 7.32 g (42.8 % of theoretical), Oil, Rf value: 0.2 (Silica gel: methylene chloride/ethanol = 95:5) II is then eluted using methylene chloride/ethanol = 96:4.
Yield: 9.28 g (54.3 % of theoretical), Oil, Rf value: 0.1 (Silica gel: methylene chloride/ethanol = 95:5) The following pure compounds were isolated from the corresponding isomer mixtures in analogous manner: tert.butyl 41-[(4-amino-2-n-butyl-benzimidazol-l-yl) methyl]biphenyl-2-carboxylate Yield: 86.1 % of theoretical.
Oil, Rf value: 0.25 (Silica gel: methylene chloride/ethanol = 99:1) ' and tert.butyl 4·-[(7-amino-2-n-buty1-benzimidazol-l-yl) methyl]biphenyl-2-carboxylate Yield: 5.0 % of theoretical, Oil, Rf value: 0.30 (Silica gel: methylene chloride/ethanol = 99:1) tert.butyl 4·-[(7-benzyloxy-2-n-butyl-4-methyl30 benz imidazol-l-yl)-methyl]biphenyl-2-carboxylate Yield: 90.5 % of theoretical, Melting point: 100-102 °C and tert.butyl 4·-[(4-benzyloxy-2-n-butyl-7-methylbenzimidazol-l-yl)-methyl]biphenyl-2-carboxylate Yield: 1.9 % of theoretical, Oil, Rf value: 0.20 (Aluminium oxide: cyclohexane/ethyl acetate = 4:1) Example 5 Tert.butyl 41-((2-n-butyl-6-methyl-benzimidazol-l-yl)methyl)biphenyl-2-carboxylate a) 2-Pentanoy1amido-5-methvl-nitro-benzene g (0.04 mol) of 2-nitro-6-methyl-aniline are dissolved in 50 ml of pyridine, cooled to 0 °C and treated with 5.3 g (0.04 mol + 10 %) of valeryl chloride while stirring. After stirring for 1 hour at ambient temperature, the mixture is poured into iced water and the crystals are filtered off under suction and dried.
Yield: 9 g (96.7 % of theoretical), Melting point: 69-71 °C ..Calculated: C 61.00 H 6.83 N 11.86 Found: 61.21 6.79 11.72 b) 2-Pentanoylamido-5-methv1-ani1irte 8.5 g (0.035 mol) of 2-pentanoylamino-5-methy1 -nitrobenzene are dissolved in 100 ml of methyl alcohol and hydrogenated at ambient temperature and 5 bar using 2 g of 10 % palladium/carbon. When the reaction is completed, the catalyst is filtered off under suction and evaporated in vacuum.
Yield: 7.1 g (94.7 % of theoretical).
Melting point: 132-134 °C (methanol) Calculated: C 69.87 H 8.80 N 13.58 Found: 69.28 8.74 13.31 c) N-(2-Pentanoylamino-5-methyl-phenyl)-2tert.butoxycarbonyl-biphenvl-41-yl-methvlamine 2.1 g (0.01 mol) of 2-pentanoylamino-5-methyl-aniline are dissolved in 10 ml of dimethylformamide and 5 ml of Ν,Ν-diisopropylethylamine, treated with 3.5 g (0.01 mol) of tert.butyl 4'-bromomethyl-biphenyl-2-carboxylate and heated at 120 °C with stirring. The reaction is complete after 2 hours and the solvent is distilled off in vacuum. The oily residue obtained is dissolved in ethyl acetate, washed with water and evaporated in vacuum after drying over sodium sulphate. A yellowish oil is obtained after column chromatography over silica gel (grain size: 0.06-0.2 mm, eluting agent: methylene chloride).
Yield: 3.8 g (80.0 % of theoretical), Oil, Rf value: 0.75 (Silica gel: methylethylketone/xylene = 1:1) Calculated: C 76.24 H 7.68 N 5.93 Found: - 76.16 7.85 5.87 d) Tert.butyl 4'-[(2-n-butyl-6-methyl-benzimidazol-lvl)-methyl1biphenyl-2-carboxvlate 3.6 g (0.076 mol) of N-(2-pentanoylamino-5methylphenyl)-2-tert.butoxycarbonyl-biphenyl-4'-ylmethylamine are taken up in 5 ml of diglyme and heated to reflux. The reaction is completed after 2 hours, the reaction product is dissolved in ethyl acetate, washed with water and evaporated in vacuum after drying over sodium sulphate. A yellowish oil is obtained after column chromatography over silica gel (grain size: 0.060.2 mm, eluting agent: methylene chloride + 1 % ethanol).
Yield: 2.1 g (61.7 % of theoretical).
Oil, Rf value: 0.6 (Silica gel: methylethylketone/xylene = 1:2) 100 Calculated: C 79.26 H 7.54 N 6.16 Found: 79.12 7.46 6.09 The following compounds are obtained in analogous manner: tert.butyl 4'-[(2-n-butyl-6-chloro-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate oil, Rf value: 0.6 (Silica gel: methylethylketone/xylene = 1:2) tert.butyl 41-[(2-n-butyl-6-methoxy-benzimidazol-l-yl)methyl)bipheny1-2-carboxylate oil, Rf value: 0.65 (Silica gel: methylethylketone/xylene = 1:2) Example 6 Tert.butyl 4'(2-n-butyl-5-methoxy-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate a) 2-Pentanovlamino-5-methoxy-nitrobenzene 4.2 g (0.025 mol) of 2-nitro-4-methoxy-aniline are dissolved in 30 ml of pyridine, cooled to 0 °C and treated with 3.3 g (0.0275 mol) of valeryl chloride with stirring. After stirring for 1 hour at ambient temperature, the mixture is poured into iced water, the crystals are filtered off under suction and dried.
Yield: 6 g (95.2 % of theoretical), Melting point: 74-75 °C C12H16N2O4 (252.27) Calculated: C 57.13 H 6.39 N 11.11 Found: 57.43 6.45 10.97 101 b) N—(2-Nitro-4-methoxy-phenyl)-N-pentanoyl-(2tert.butoxvcarbonvl-biphenvl-4'-vl)-methvlamine 2.5 g (0.01 mol) of 2-pentanoylamino-5-methoxynitrobenzene are dissolved in 30 ml of dimethylformamide, treated with 550 mg (0.11 mol) of sodium hydride (50 % in oil) and stirred for 30 minutes at 80 °C. 3.5 g (0.01 mol) of tert.butyl 4’-bromomethylbiphenyl-2-carboxylate are then added and stirred for a further 2 hours at 80 °C. The solvent is distilled off in vacuum, the oily residue obtained is dissolved in ethyl acetate, washed with water and evaporated in vacuum after drying over sodium sulphate. A yellowish oil is obtained after column chromatography (silica gel: 0.060.2 mm, eluting agent: methylene chloride).
Yield: 4.0 g (78.4 % of theoretical), Oil, Rf value: 0.8 (Silica gel: methylethylketone/xylene = 1.:2) 20 C30H„N2O6 (518.61) Calculated: C 69.48 H 6.61 N 5.40 Found: 69.31 6.53 5.39 c) N—(2-Amino-4-methoxy—phenyl)-N-pentanoyl-(22$ tert.butoxvcarbonvl-biphenvl-41-vl)-methvlamine 3.8 g (0.007 mol) of N-(2-nitro-4-methoxy-phenyl)-Npentanoyl-(2-tert.butoxycarbonyl-biphenyl-4 *-yl)methylamine are dissolved in 100 ml of methanol and hydrogenated at ambient temperature and 5 bar in the presence of 1 g of 70 % palladium/carbon. After the reaction is completed, the catalyst is filtered off under suction and evaporated in vacuum.
Yield: 3.2 g (93.6 % of theoretical), ’5 Oil, Rf value: 0.5 (Silica gel: methylethylketone/xylene = 1:2) 102 C30H36N2O4 (488.63) Calculated: C 73.74 H 7.43 N 5.73 Found: 73.59 7.40 5.72 d) Tert.butyl 4'-[(2-n-butyl-5-methoxy-benzimidazol-lvl1-methvl1biphenvl-2-carboxvlate g (0.006 mol) of N-(2-amino-4-methoxy-pheny1)-Npentanoyl-(2-tert.butoxycarbonyl-biphenyl-4·-yl)methylamine are dissolved in 100 ml of glacial acetic acid and heated to reflux with stirring. After one hour the solvent is distilled off and the resulting oil is chromatographed for further purification over silica gel (grain size: 0.06-0.2 mm, eluting agent: methylene chloride/ethanol = 19:1).
Yield: 2.3 g (82.1 % of theoretical), Oil, R£ value: 0.7 (Silica gel: ethyl acetate/ethanol/ammonia = 90:10:1) C30H3«N2O3 (470.61) Calculated: C 76.56 H 7.28 N 5.95 Found: 76.36 7.31 5.79 The following compounds are obtained in analogous manner: tert.butyl 4 ’ -( (2-!>n-butyl-5-chloro-benzimidazol-l-yl) methyl]biphenyl-2-carboxylate oil, Rf value: 0.7 (Silica gel: ethyl acetate/ethanol/ammonia = 90:10:1) tert.butyl 4·—[(5-amino-2-n-butyl-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate oil, Rf value: 0.5 (Silica gel: ethyl acetate/ethanol/ammonia - 90:10:1) tert.butyl 4·-[(2-n-butyl-5-methyl-benzimidazol-l-yl)103 methyl]biphenyl-2-carboxylate oil, Rf value: 0.8 (Silica gel: ethyl acetate/ethanol/ammonia = 90:10:1) tert.butyl 4'-[(2-n-butyl-7-cyano-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate oil, Rf value: 0.49 (Silica gel: methylene chloride/ethanol = 19:1) tert.butyl 4'-[(2-n-butyl-5,7-di£luoro-benzimidazol-lyl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.27 (Silica gel: methylene chloride/ethanol = 50:1) tert.butyl 4'-((2-n-butyl-5-acetyl-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate oil, Rc value: 0.30 (Silica gel: methylene chloride/ethanol = 50:1) tert. butyl 4 ’ - [ (2-n-butyl-6-dimethylamino-benzimidazoll-yl )-methyl]biphenyl-2-carboxylate oil, Rf value: 0.60 (Silica gel: methylene chloride/ethanol = 19:1) tert.butyl 4·-[(7-amino-2-n-butyl-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate oil, Rf value: 0.30 (Aluminium oxide: methylene chloride/ethanol = 99:1) tert.butyl 4’-[(6-(N-benzyl-methylamino)-2-n-butylbenz imidazol-l-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.40 (Silica gel: methylene chloride/ethanol = 19:1) tert. butyl 41 - [ (2-n-butyl-5-dimethylamino-sulphonyl-3-Noxido-benz imidazol-l-yl) -methyl ] biphenyl-2-carboxylate (prepared by incomplete reduction of the nitro group and 104 subsequent cyclisation) melting point: 59-62 °C tert.butyl 4'-[ (7-benzyloxy-2-n-butyl-benzimidazol-lyl)-methyl)biphenyl-2-carboxylate oil, Rf value: 0.50 (Silica gel: methyl ethy Ike tone/ xylene = 1:1) tert.butyl 4*-[ (4-benzyloxy-2-n-butyl-benzimidazol-l10 yi)-methyl]hiphenyl-2-carboxylate oil, Rf value: 0.65 (Silica gel: methylethylketone/ xylene = 1:4) tert.butyl 4'-[(2-n-butyl-7-methoxy-benzimidazol-l-yl)15 methyl]biphenyl-2-carboxylate oil, Rf value: 0.80 (Silica gel: methylethylketone/xylene = 1:1) tert.butyl 4 * -[ (2-n-butyl-4-methoxy-benzimidazol-l-yl)20 methyl]biphenyl-2-carboxylate oil, Rf value: 0.70 (Silica gel: methylethylketone/xylene = 1:2) tert.butyl 4'-[(2,5-di-n-butyl-benz imidazol-l-yl)25 methyHbiphenyl-2-carboxylate tert.butyl 4‘-[ (2,6-di-n-butyl-benzimidazol-l!-yl)methyl)biphenyl-2-carboxylate tert.butyl 4'-[ (6-benzyloxy-2-n-butyl-benzimidazol-lyl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.40 (Silica gel: methylethylketone/xylene = 1:2) tert.butyl 4(2-n-butyl-6-methylamino-benzimidazol-lyl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.10 (Silica gel: methylene 105 chloride/ethanol = 50:1) tert.butyl 4·-[(2-n-butyl-6-cyclohexylaminobenzimidazol-1-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.20 (Silica gel: ethyl acetate/petroleum ether = 60:40) tert.butyl 4’-[(2-n-butyl-6-(3-cyclohexyl-piperidino)benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.65 (Silica gel: methylene chloride/ethanol = 9:1) tert.butyl 4’-[(2-n-butyl-6-phthalimino-benzimidazol-lyl)-methyl]biphenyl-2-carboxylate melting point: 182-184 °C tert.butyl 41-[(2-n-butyl-6-(n-pentylamino)-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.70 (Silica gel: methylethylketone/xylene - 1:1) Example 7 Tert.butyl 4·-[(2-n-butyl-5-(n-butylaminocarbonylamino)benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate 106 2.0 g (4.4 mmol) of tert.butyl 4’-[(5-amino-2-n-butylbenzimidazol-l-yl)-methyl]biphenyl-2-carboxylate are dissolved in 50 ml of tetrahydrofuran and treated with 2.0 ml of triethylamine and 2.0 ml of n-butylisocyanate.
The reaction mixture is heated at reflux for 4 hours, rotary evaporated, and the residue is purified over a silica gel column (grain size: 0.063 mm-0.2 mm, eluting agent: methylene chloride/0-2 % ethanol). The homogeneous fractions are evaporated to dryness.
Yield: 2.1 g (86.4 % of theoretical), Oil, Rf value: 0.45 (Silica gel: methylene chloride/ethanol = 19:1) The following compounds are obtained in analogous manner: tert.butyl 4'-[(2-n-butyl-6-phenylaminocarbonylaminobenzimidazol-l-yl)-methyl] biphenyl-2-carboxylate amorphous substance, Rf value: 0.30 (Silica gel: methylene chloride/ethanol = 19:1) tert.butyl 4*-[(2-n-butyl-6-cyclohexylaminocarbonylamino-benz imidazol-l-yl) -methyl ] biphenyl-2 -carboxylate amorphous substance, Rf value: 0.25 (Silica gel: methylene chloride/ethanol = 19:1) tert.butyl 4 *-[(2-n-butyl-4-ethylaminocarbonylaminobenzimidazoi-l-yl)-methyl ] biphenyl-2-carboxylate amorphous substance, Rf value: 0.50 (Silica gel: methylene chloride/ethanol = 19:1) tert.butyl 4'-((6-aminocarbonylamino-2-n-butylbenzimidazol-l-yl) -methyl ] biphenyl-2-carboxylate melting point: 210-211 °C tert.butyl 41-[(2-n-buty1-6-(n-hexylaminocarbonylamino)benz imidazol-l-yl) -methyl J biphenyl-2-carboxylate 107 melting point: 142-143 °C tert.butyl 4 * -[(2-n-butyl-4-cyclohexylaminocarbonylamino-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate melting point: 104-106 °C (amorphous) tert.butyl 4'-[(2-n-butyl-5-cyclohexylaminocarbonylamino-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate melting point: 118-120 °C (amorphous) ethyl 4'-[(2-n-butyl-7-cyclohexylaminocarbonylaminobenzimidazol-l-yl)-methyl]biphenyl-2-carboxylate melting point: 152-154 °C tert.butyl 4·-[(6-aminothiocarbonylamino-2-n-butylbenzimidazol-l-yl)-methyl]biphenyl-2-carboxylate melting point: 175-176 °C tert.butyl 4 · - [ (2-n-butyl-6-cyclohexylaminothiocarbonyl amino-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate melting point: 91-93 °C (amorphous) tert.butyl 41-((5-aminothiocarbonylamino-2-n-butylbenzimidazol-l-yl)-methyl]biphenyl-2-carboxylate melting point: 196-197 °C tert.butyl 4’-[(2-n-butyl-6-benzylaminocarbonylaminobenzimidazol-l-yl)-methyl]biphenyl-2-carboxylate melting point: 163-165 °C tert.butyl 4·-((6-allylaminocarbonylamino-2-n-butylbenz imidazol-l-yl)-methyl]biphenyl-2-carboxylate oil, R£ value: 0.10 (Silica gel: methylene chloride/ethanol = 19:1) ethyl 4 · — [(2-n-butyl-6-(tetrahydropyran-2-yl-aminocarbonylamino) -benzimidazol-l-yl)-methyl]biphenyl-2108 carboxylate melting point: 86-88 °C (amorphous) tert.butyl 4' -((2-n-butyl-6-(tetrahydropyran-2-yl5 aminocarbonylamino)-benzimidazol-l-yl)-methyl]biphenyl2-carboxylate oil, Rf value: 0.20 (Silica gel: methylene chloride/ethanol = 19:1) tert.butyl 4·-[(2-n-butyl-6-(N-methylaminocarbonyl-npentylamino)-benzimidazol-l-yl)-methyl]biphenyl-2carboxylate oil, Rf value: 0.30 (Silica gel: methylethylketone/xylene = 5:2) ·-[ (2-n-butyl-6-cyclohexylaminocarbonylamino-benzimidaz ol-l-y1)-methyl] -2-phthalimino-biphenyl oil, Rf value: 0.45 (Silica gel: methylene chloride/ethanol = 9:1) *-[(6-adamant-l-yl-aminocarbonylamino)-2-n-butyl-benzim idazol-l-yl)-methyl]biphenyl-2-carboxylic acid melting point: 251-253 °C tert.butyl 4·-[(6-(adamant-l-yl-aminocarbonylamino)-2-nbutyl-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate melting point: 196-198 °C tert.butyl 4·-[(2-n-butyl-6-(N-methylaminocarbonyl30 methylamino) -benz imidazol-l-yl) -methyl ] biphenyl-2carboxylate oil, Rf value: 0.30 (Silica gel: methylethylketone/xylene = 5:2) tert.butyl 4'-[(2-n-butyl-6-(N—(n-butylaminocarbonyl)methylamino) -benz imidazol-l-yl) -methyl]biphenyl-2carboxylate 109 oil, Rf value: 0.70 (Silica gel: methylethylketone/xylene = 5:2) tert.butyl 4 * — ((2-n-butyl-5-(N-methylaminocarbonyl-npentylamino)-benzimidazol-l-yl)-methyl]bipheny1-2carboxylate oil, Rf value: 0.45 (Silica gel: methylethylketone/xylene = 1:2) tert.butyl 4'-[(6-(n-butylaminocarbonylamino)-2-n-butylbenzimidazol-l-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.7 (Silica gel: ethyl acetate/ethanol/ammonia = 90:10:1) tert.butyl 4'-[(2-n-butyl-6-(N-cyclohexylaminocarbonylmethylamino)-benzimidazol-l-yl)-methyl]bipheny1-2carboxylate oil, Rf value: 0.7 (Silica gel: methylethylketone/xylene = 5:2) tert.butyl 4·-[(2-n-butyl-6-(N-(n-butylaminocarbonyl)methylamino) -benzimidazol-l-yl) -methyl]biphenyl-2carboxylate oil, Rf value: 0.55 (Silica gel: methylethylketone = 5:2) tert.butyl 4’-[(2-n-butyl-6-(N-cyclohexylaminocarbonyln-penty lamino) -benzimidazol-l-yl) -methyl ]biphenyl-2carboxylate oil, Rf value: 0.8 (Silica gel: methylethylketone = 5:2) tert.butyl 4’-[(2-n-butyl-6-(N-(n-hexylaminocarbonyl)cyclohexylamino)-benzimidazol-l-yl)-methyl]biphenyl-2carboxylate oil, Rf value: 0.40 (Aluminium oxideplate:ethyl acetate/petroleum ether = 3:7) tert.butyl 4'-[(2-n-butyl-6-(N-cyclohexylaminocarbonyl110 cyclohexylamino)-benzimidazol-l-yl)-methyl Jbiphenyl-2carboxylate oil, R£ value: 0.40 (Aluminium oxide: ethyl acetate/petroleum ether = 4:1) tert. butyl 4 ’ - [ (2-n-butyl-'6- (N- (n-butylaminocarbonyl) cyclohexylamino) -benzimidazol-l-yl) -methyl]biphenyl-2carboxylate oil, Rf value: 0.35 (Silica gel: ethyl acetate/petroleum ether = 4:1) tert.butyl 4’-[(2-n-butyl-6-(N-methylaminocarbonylcyclohexylamino) -benzimidazol-l-yl) -methyl]biphenyl-2carboxylate oil, Rf value: 0.45 (Aluminium oxide: ethyl acetate/petroleum ether = 7:3) tert.butyl 4'-[(2-n-butyl-6-(N-methylaminocarbonylbenzylamino) -benzimidazol-l-yl) -methyl]biphenyl-2carboxylate oil, Rf value: 0.45 (Aluminium oxide: ethyl acetate/petroleum ether - 6:4) tert.butyl 4'-[(2-n-butyl-6-(N-(n-hexylaminocarbony1)benzylamino) -benzimidazol-l-yl) -methyl] biphenyl-2-carbox ylate oil, Rf value: 0.50 (Aluminium oxide: ethyl acetate/petroleum ether = 4:6) tert.butyl 4'-[(2-n-butyl-6-(N-cyclohexylaminocarbonyln-butyl eunino) -benzimidazol-l-yl) -methyl ] biphenyl -2carboxylate melting point: 106-108 °C (amorphous) tert.butyl 4·-[(2-n-butyl-6-(N-cyclohexylaminocarbony1benzylamino)-benzimidazol-l-yl)-methyl)biphenyl-2carboxylate 111 oil, Rf value: 0.60 (Silica gel: ethyl acetate/petroleum ether = 6:4) tert.butyl 4’-[(2-n-butyl-6-(N-(2-trifluoromethylphenylaminocarbony1)-methylamino)-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.90 (Silica gel: methylethylketone/xylene = 5:2) tert.butyl 4’-((2-n-butyl-6-(N-cyclohexylaminocarbonyln-hexylamino)-benzimidazol-l-yl)-methyl]biphenyl-2carboxylate oil, Rf value: 0.70 (Silica gel: ethyl acetate/petroleum ether = 6:4) tert.butyl 4’-[(2-n-butyl-6-(N-cyclohexylaminocarbonyln-propylamino)-benzimidazol-l-yl)-methyl]biphenyl-2carboxylate oil, Rf value: 0.50 (Silica gel: ethyl acetate/petroleum ether = 6:4) tert.butyl 4'-[(2-n-butyl-6-(N-cyclohexylaminocarbony1ethylamino)-benzimidazol-l-yl)-methyl)biphenyl-2carboxylate oil, Re value: 0.20 (Silica gel: ethyl acetate/petroleum ether = 6:4) tert.butyl 4'-[(2-n-butyl-6-(N-cyclohexylaminocarbonylN-(2-phenylethyl)-amino)-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.55 (Silica gel: ethyl acetate/petroleum ether = 6:4) tert.butyl 41-[(2-n-butyl-6-(N-(n-hexylaminocarbonyl)-N(2-phenylethyl)-amino)-benzimidazol-l-yl)-methyl]biphenyl-2 -carboxylate oil, Rf value: 0.20 (Silica gel: ethyl acetate/petroleum 112 ether = 7:3) tert.butyl 4 (2-(l-trans-butenyl)-6-cyclohexylaminocarbonylamino-benzimidazol-l-yl) -methyl]biphenyl-2carboxylate oil, Rf value: 0.20 (Aluminium oxide: methylene chloride/ethanol - 50:1) tert.butyl 4'-[(2-n-butyl-6-(N-(dimethylaminocarbony1) n-penty lamino) -benzimidazol-l-yl) -methyl]biphenyl-2carboxylate oil, Rc value: 0.50 (Silica gel: methylethylketone/xylene = 1:1) ·-[ (2—n-butyl—6—cyclohexylaminocarbonylamino— benzimidazol-l-yl) -methyl ] -2- (1H-tripheny 1-methy 1tetrazol-5-yl)-biphenyl melting point: 183-187 °C 4'-[ (2-n-butyl-6-(N-cyclohexylaminocarbonylmethylamino)benzimidazol-l-yl) -methyl]-2-(lH-tetrazol-5-yl) -biphenyl oil, Rf value: 0. .(Silica gel: = : ) tert.butyl 4’-((2-n-butyl-6-cyclohexylaminocarbonyloxybenz imidazol-1-yl) -methyl ]biphenyl-2-carboxylate melting point: 76-78 °C (amorphous) tert.butyl 4 *-[(2-n-butyl-6-(N-methylaminocarbonyl-N-(3cyclohexyl-n-propyl) -amino) -benzimidazol-l-yl) -methyl]bi pheny1-2-carboxylate oil, r£ value: 0.15 (aluminium oxide: petroleum ether/ethyl acetate = 2:3) (2-n-butyl-6-(N-cyclohexylaminocarbonyl-methylamino) -benzimidazol-l-yl) -methyl ] -l-cyano-2-phenylnaphthalene 113 tert.butyl 4' - [(2-n-propyl-6-(N-cyclohexylaminocarbony1 methylamino)-benzimidazol-l-yl)-methyl]-2-phenylnaphthalene-l-carboxylate tert.butyl 4'-[ (2-n-butyl-6-(N-(n-dodecylaminocarbonyl) methylamino)-benzimidazol-l-yl)-methyl]biphenyl-2carboxylate oil, Rf value: 0.40 (aluminium oxide: petroleum ether/ethyl acetate = 3:7) tert.butyl 4 ' - [ (2-n-butyl-6-(N-(cyclohexylaminocarbonyl) -n-octylamino) -benzimidazol-l-yl) -methyl]bipheny1-2-carboxylate oil, Rf value: 0.35 (aluminium oxide:petroleum ether/ethyl acetate = 3:2) tert. butyl 4 * - [ (2-n-butyl-6- (N- (n-octylaminocarbonyl, methylamino)-benzimidazol-l-yl)-methyl]biphenyl-2carboxylate Oil, Rf value: 0.35 (aluminium oxide: petroleum ether/ethyl acetate = 2:3) 114 Example 8 Tert.butyl 4' - [ (2-n-buty 1-4-butanoylamino-benzimidazoll-yl )-methyl]biphenyl-2-carboxylate 1.6 g (3.5 mmol) of tert.butyl 4'-[ (4-amino-2-n-butylbenzimidazol-l-yl) -methyl ] biphenyl-2-carboxylate are dissolved in 30 ml of pyridine and 0.52 ml (5.0 mmol) of butyryl chloride is added dropwise at ambient temperature with stirring. After one hour the solvent is distilled off and the residue is mixed with about 20 ml of diethylether. The precipitate is filtered off under suction and dried at 50 °C in vacuum.
Yield: 1.75 g (94.6 % of theoretical).
Melting point: 167-168 °C The following compounds are obtained in analogous manner: tert.butyl 4' -[ (2-n-butyl-5-acetamino-benzimidazol-lyl)-methyl)biphenyl-2-carboxylate oil, R£ value: 0.70 (Silica gel: methylene chloride/ethanol = 9:1) tert.butyl 4 ·-[ (2-n-butyl-5-butanoylamino-benzimidazol1-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.80 (Silica gel: ethyl acetate/ethanol/ammonia — 90:10:1) tert. butyl 4 1 - [ (2-n-butyl-5-methanesulphonaminobenz imidazol-l-yl) -methyl ] biphenyl-2-carboxylate oil, Rf value: 0.75 (Silica gel: ethyl acetate/ethanol/ammonia — 90:10:1) tert.butyl 4 · -[ (2-n-butyl-6-isopropylsulphonaminobenz imidazol- 1-y 1) -methyl ] biphenyl-2-carboxylate 115 amorphous substance, Rf value: 0.55 (Silica gel: methylene chloride/ethanol = 19:1) tert.butyl 4'—[(2-n-butyl-6-ethoxycarbonylaminobenzimidazol-l-yl) -methyl ] biphenyl-2-carboxylate amorphous substance, Rf value: 0.30 (Silica gel: methylene chloride/ethanol = 19:1) tert.butyl 4·-[(2-n-butyl-5-(tert.butoxycarbonylaminoacetamino) -benzimidazol-l-yl) -methyl ]biphenyl-2carboxylate melting point: 101-103 °C (amorphous) tert.butyl 4 · -[(2-n-butyl-6-(N-butanoyl-methylamino)benzimidazol-l-yl) -methyl ]biphenyl-2-carboxylate oil, Rf value: 0.70 (Silica gel: methylene chloride/ethanol = 19:1) ethyl 4 ' - [ (2-n-butyl-7-butanesulphonylaminobenzimidazol-l-yl) -methyl) biphenyl-2-carboxylate oil, Rf value: 0.50 (Silica gel: methylene chloride/ethanol = 19:1) ethyl 4 ’ — [ (2-n-buty 1-5-propanoylamino-benzimidazol-lyl)-methyl ] biphenyl-2-carboxylate melting point: 221-223 °C tert.butyl 4 · -[ (6-acetamino-2-n-butyl-benzimidazol-lyl )-methyl]biphenyl-2-carboxylate melting point: 192-194 °C tert.butyl 4 · - [ (2-n-butyl-6-propanoylamino-benzimidazol-l-yl) -methyl ] biphenyl-2-carboxylate melting point: 133-135 °C tert.butyl 41-[(6-butanoylamino-2-n-butyl-benzimid-azol 1-yl)-methyl]biphenyl-2-carboxylate 116 melting point: 127-129 °C tert.butyl 4 1 - [(2-n-butyl-6-n-pentanoylamino-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.6 (Silica gel: methylene chloride/ethanol = 19:1) tert.butyl 41-[(2-n-butyl-6-dimethylaminocarbonylaminobenzimidazol-l-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.4 (Silica gel: methylethylketone/xylene = 5:2) tert.butyl 4'-[(2-n-butyl-6-(N-(dimethylaminocarbonyl)methylamino)-benzimidazol-l-yl)-methyl]biphenyl-2carboxylate oil, Rf value: 0.45 (Silica gel: methylene chloride/ethanol = 19:1) tert.butyl 4··-[ (2-n-butyl-6-phenylacetamino-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate Rf value: 0.30 (Silica gel: methylene chloride/ethanol 50:1) melting point: 178-180 °C tert.butyl 4·-[(2-n-butyl-6-cyclohexylacetaminobenzimidazol-l-yl)-methyl]biphenyl-2-carboxylate Rf value: 0.30 (Silica gel: ethyl acetate/petroleum ether = 4:1) melting point: 64-66 °C (amorphous) tert.butyl 4’-[(2-n-butyl-6-cyclohexylcarbonylaminobenzimidazol-l-yl) -methyl ]biphenyl-2-carboxylate r£ value: 0.70 (Silica gel: ethyl acetate/petroleum ether = 9:1) melting point: 72-76 °C (amorphous) tert.butyl 4’-[(6-benzyloxycarbonylamino-2-n-butyl117 benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate Rf value: 0.80 (Silica gel: ethyl acetate/petroleum ether = 9:1) melting point: 84-86 °C 5 tert.butyl 4'-[(2-n-butyl-6-cyclohexylmethylaminocarbonyl-benzimidazol-l-yl)-methyl]biphenyl-2carboxylate oil, Rf value: 0.45 (Silica gel: petroleum ether/ethyl 10 acetate/ethanol = 2.5:2.5:0.5) tert.butyl 4 · - [(2-n-buty1-6-cyclohexylaminocarbonylbenz imidazol-l-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.50 (Silica gel: petroleum ether/ ethyl acetate/ethanol = 2.5:2.5:0.5) tert.butyl 4(2-n-butyl-6-(N-methyl-n-butyl-aminocarbonyl )-benzimidazol-l-yl)—methyl]biphenyl-2carboxylate oil, Rf value: 0.40 (Silica gel: petroleum ether/ethyl acetate/ethanol = 6:3:1 + 1 % glacial acetic acid) tert.butyl 4·-[(2-n-butyl-5-(n-butylaminocarbonyl)benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: .0.75 (Silica gel: petroleum ether/ethyl acetate = 1:2 + 1 % glacial acetic acid) tert.butyl 4'-[(2-n-butyl-6-(2-isopropyl-5-methyl-cyclohexyloxycarbonylamino)-benzimidazol-l-yl)-methyl]bi30 phenyl-2-carboxylate oil, Rf value: 0.45 (Silica gel: ethyl acetate/petroleum ether = 60:40) tert.butyl 4‘-[(2-n-buty1-6-(N-ethoxycarbonyl-cyclo35 hexylamino)-benzimidazol-l-yl)-methyl]biphenyl-2carboxylate oil, Rf value: 0.65 (Silica gel: ethyl acetate/petroleum 118 ether = 6:4) tert. butyl 4 · - [ (2-n-butyl-6-cyclohexylacetaminobenzimidazol-l-yl) -methyl]biphenyl-2-carboxylate melting point: 65-66 °C (amorphous) tert. butyl 4' - [ (2-n-butyl-6- (N-ethoxycarbonylbenzylamino) -benzimidazol-l-yl) -methyl ] biphenyl-2carboxylate oil, Rf value: 0.60 (Silica gel: ethyl acetate/petroleum ether = 7:3) tert.butyl 4·-((2-n-butyl-6-(n-hexyloxycarbonylamino)benzimidazol-l-yl) -methyl ]biphenyl-2-carboxylate oil, Rf value: 0.55 (Silica gel: ethyl acetate/petroleum ether = 6:4) tert.butyl 4'·-[(2-n-butyl-6-(5,7-dioxo-lH,3H-imidazo[1,5-c]thiazol-6-yl) -benzimidazol-l-yl) -methyl ] biphenyl2-carboxylate oil, Rf value: 0.55 (Aluminium oxide: ethyl acetate/petroleum ether = 7:3) tert .butyl 4' - [ (2-n-butyl-6- (N— (n-butanoyl) -n-butylamino) -benzimidazol-l-yl) -methyl ]biphenyl-2-carboxylate oil, Rf value: 0.60 (Silica gel: ethyl acetate/petroleum ether = 6:4) tert.butyl 4'-[ (2-n-butyl-6-(N-(4-methoxycarbonylthiazolidin-3-ylcarbonyl) -n-butylamino) -benzimidazol-lyl )-methyl]biphenyl-2-carboxylate oil, Rf value: 0.55 (Silica gel: ethyl acetate/petroleum ether = 6:4) tert.butyl 4’-[(2-n-butyl-6-(N-cyclohexylcarbonyl-nhexylamino)-benzimidazol-l-yl) -methyl)biphenyl-2carboxylate 119 oil, Rf value: 0.55 (Silica gel: ethyl acetate/petroleum ether = 6:4) tert.butyl 4'-[(2-n-butyl-6-(N-cyclohexylcarbonylmethylamino)-benzimidazol-l-yl)-methyl]biphenyl-2carboxylate oil, Rf value: 0.70 (Silica gel: ethyl acetate/petroleum ether = 6:4) tert.butyl 4·-[(2-n-butyl-6-(N-(n-butanoyl)-n-pentylamino) -benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.60 (Silica gel: methylethylketone/xylene = 1:1) tert.butyl 4'-[(2-n-butyl-6-isopropylcarbonylaminobenzimidazol-l-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.15 (Silica gel: ethyl acetate/petroleum ether = 7:3) tert.butyl 4'-[(2-n-buty1-6-(N-ethoxycarbonylmethylamino)-benzimidazol-l-yl)-methyl]biphenyl-2carboxylate oil, Rc value: 0.35 (Silica gel: ethyl acetate/petroleum ether = 6:4) tert.butyl 4'(2-n-butyl-6-(N-ethoxycarbonyl-npentylamino)-benzimidazol-l-yl)-methyl]biphenyl-2carboxylate oil, Rf value: 0.70 (Silica gel: methylethylketone/xylene = 1:1) tert.butyl 4'-[(2-n-buty1-6-(N-(dimethylaminocarbonyl)benzylamino)-benzimidazol-l-yl)-methyl]biphenyl-2carboxylate oil, Rf value: 0.45 (Silica gel: ethyl acetate/petroleum ether = 4:1) 120 tert. butyl 4 ’ - [ (2-n-butyl-6-diethylaminocarbonylaminobenzimidazol-l-yl) -methyl]biphenyl-2-carboxylate oil, R£ value: 0.20 (Silica gel: ethyl acetate/petroleum ether = 9:1) tert. butyl 4' - [ (2-n-buty 1-6- (dimethylaminoacetamino) benzimidazol-l-yl) -methyl ]biphenyl-2-carboxylate oil, Rf value: 0.40 (Silica gel: methylethylketone/xylene = 5:2) tert.butyl 4 ' -[(2-n-butyl-6-(2,2-dimethylpropionylamino) -benzimidazol-l-yl) -methyl] biphenyl-2-carboxylate oil, Rf value: 0.60 (Silica gel: ethyl acetate/petroleum ether = 9:1) tert. butyl 4 * - [ (2-n-butyl-6-cyclopentylcarbonylaminobenz imidazol-l-yl) -methyl ]biphenyl-2-carboxylate oil, Rf value: 0.35 (Silica gel: ethyl acetate/petroleum ether = 7:3) y' tert. butyl 4 · - [ (2-n-butyl-6-cyclopropylcarbonylaminobenz imidazol-l-yl) -methyl ] biphenyl-2 -carboxylate melting point: 175-177 °C tert.butyl 4'-[ (2-n-butyl-6-cyclohexyloxycarbonylaminobenzimidazol-l-yl) -methyl] biphenyl-2-carboxylate melting point: 68-70 °C (amorphous) (2-n-butyl-6-dimethylaminocarbonylaminobenzimidazol-l-yl) -methyl ] -2- (1-triphenylmethyltetrazol-5-yl)-biphenyl oil, Rf value: 0.75 (Silica gel: ethyl acetate/ethanol/ammonia = 90:10:1) tert. butyl 4 ’ - [ (2-n-butyl-6-morpholinocarbonylaminobenz imidazol-1-yl) -methyl] biphenyl-2-carboxylate melting point: 74-76°C 121 tert.butyl 4'-[(2-n-butyl-6-pyrrolidinocarbonylaminobenzimidazol-l-yl)-methyl]biphenyl-2-carboxylate tert.butyl 4'-[(2-n-butyl-6-dimethylaminocarbonyloxybenz imidazol-1-yl)-methyl]biphenyl-2-carboxylate melting point: 137-138’C tert.butyl 4’-[(2-n-butyl-6-(N-acetyl-n-octylamino)benz imidazol-1-yl)-methyl]biphenyl-2-carboxylate Oil, Rf value: 0.25 (silica gel: ethyl acetate/petroleum ether = 7:3) Example 9 4' -((2-Hydroxybenzimidazol-l-yl) -methyl] biphenyl-2-carbo xylic acid 0.9 g (2.25 mmol) of tert.butyl 4 * -[(2-hydroxybenzimidazol-l-yl) -methyl]biphenyl-2-carboxylate are dissolved in 10 ml of methyleiie chloride and treated with 10 ml of trifluoroacetic acid. The solution is stirred for 2 hours at ambient temperature and then evaporated to dryness on a rotary evaporator. The oily residue is dissolved in 50 ml of methylene chloride and extracted by shaking twice using water. The organic phase is dried using magnesium sulphate and evaporated to dryness. The crystalline residue thus obtained is mixed with a small amount of diethylether, filtered under suction and dried in vacuum at 50 °C.
Yield: 0.75 g (97.4 % of theoretical), Melting point: 303-304 °C C2iH16N2O3 (344.37) Calculated: C 73.24 H 4.68 N 8.13 Found: 73.07 4.81 7.95 The following compounds are obtained in analogous manner: 122 · -[ (2,5-di-n-butylbenzimidazol-l-yl) -methyl)biphenyl-2carboxylic acid M.p.: 199-201*C 4’-[(2,6-di-n-butylbenzimidazol-l-yl)-methyl]biphenyl-2carboxylic acid M.p.: 188-190‘C Example 10 ’-[ (2-n-Butyl-6-methoxybenzimidazol-l"yl)-methyl]biphen yl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4’-[(2-n-butyl-6-methoxybenzimidazol-l-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid. Yield: 73.9 % of theoretical, Oil, Rf value: 0.6 (Silica gel: ethyl acetate/ethanol/ammonia = 50:45:5) C26H26N2O3 (414.51) Calculated: C 75.34 H 6.23 N 6.76 Found: 75.27 6.03 6.52 Example ll 4·-[(2-n-Butyl-4-methyl-7-(2-diethylamino-ethoxy)benzimidazol-l-yl) -methyl]biphenyl-2-carboxylic acid dihydrate Prepared in analogous manner to Example 9 from tert.butyl 4·-[(2-n-butyl-4-methy1-7-(2-diethylaminoethoxy) -benzimidazol-l-yl) -raethyl)biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 94.2 % of theoretical, Melting point: 94-96 °C C32H39N3O3 X 2 H2O (549.72) Calculated: C 69.92 H 7.88 N 7.64 Found: 69.62 7.60 7.40 123 Example 12 4'-[(2-Ethylthio-benzimidazol-l-yl)-methyl)biphenyl-2carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'—[(2-ethylthio-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 92.9 % of theoretical, Melting point: 197-198 °C C23H20N2O2S (388.48) Calculated: C 71.11 H 5.19 N 7.21 S 8.25 Found: 71.12 5.13 7.23 8.31 Example 13 41 -[ (2-n-Propylthiomethyl-benzimidazol-l-yl) -methyl] biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-propylthiomethyl-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid. Yield: 96.8 % of theoretical.
Melting point: 139-141 °C C25H24N2O2S (416.54) Calculated: C 72.09 H 5.81 N 6.73 S 7.70 Found: 71.82 5.83 6.57 7.43 Example 14 4’-[(2-Methyl-benzimidazol-l-yl)-methyl]biphenyl-2carboxylic acid x 0.33 HC1 Prepared in analogous manner to Example 9 from tert.butyl 41-[(2-methyl-benzimidazol-l-yl)-methyl]bi124 phenyl-2-carboxylate and trifluoroacetic acid.
Yield: 93.2 % of theoretical, Melting point: 255-256 °C C22H18N2O2 X 0.33 HC1 (354.54) calculated: C 74.53 H 5.21 N 7.90 Cl 3.32 Found: 74.60 5.14 8.16 3.40 Example 15 4·-[(2-Methylmercapto-benzimidazol-l-yl)-methyl]biphenyl -2 -carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-methylmercapto-benz imidazol-l-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid. Yield: 88.2 % of theoretical, Melting point: 197-199 °C C22Hi8N2O2S (374.46) Calculated: C 70.57 H 4.84 N 7.48 S 8.56 Found: 70.30 4.87 7.25 8.25 Example 16 4'-[(2-Methyl-5-and 6-nitro-benzimidazol-l-yl)-methyl]bipheny1-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4 * -[(2-methyl-5-and 6-nitro-benzimidazol-lyl)-methyl ]biphenyl-2-carboxy late and trifluoroacetic acid.
Yield: 71.1 % of theoretical, Melting point: 285-288 °C C22H17N3O, (387.39) Calculated: C 68.21 H 4.42 N 10.85 Found: 67.96 4.40 10.83 125 Example 17 · — [(2-Methy1-5-and 6-butanoylamino-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4·-[(2-methyl-5-and 6-butanoylaminobenzimidazol-l-yl) -methyl)biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 79.5 % of theoretical, Melting point: 261-262 °C C26H25N3O3 (427.50) Calculated: C 73.05 H 5.89 N 9.83 Found: 72.85 5.90 9.80 Example 18 4'-[ (2-(2-Methylpropyl) -benzimidazol-l-yl) -methyl]biphen yl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-(2-methylpropyl)-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid. Yield: 71.9 % of theoretical, Melting point: 211-212 °C C25H2,N2O2 (384.48) Calculated: C 78.10 H 6.29 N 7.29 Found: 77.95 6.22 7.15 Example 19 * -[(2-Methoxymethyl-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from 126 tert.butyl 4'-[(2-methoxymethyl-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid. Yield: 80.3 % of theoretical, Melting point: 195-197 °C C23H20N2O3 (372.43) Calculated: C 74.18 H 5.41 N 7.52 Found: 73.99 5.39 7.43 Example 20 4·-[(2-(2-Pyridyl)-benzimidazol-l-yl)-methyl]biphenyl-2carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4’(2-(2-pyridyl)-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid. Yield: 50.0 % of theoretical, Melting point: 262-264 °C C26HieM3O2 (405.45) Calculated: C 77.02 H 4.72 N 10.36 Found: 77.21 4.58 10.20 Example 21 *-[(5-and 6-Methy1-benzimidazol-l-yl)-methyl]bi-phenyl2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-[(5-and 6-methyl-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid. Yield: 92.0 % of theoretical, Melting point: 228-230 °C C22HleN2O2 (342.396) Calculated: C 77.17 H 5.30 N 8.18 Found: 76.94 5.23 7.93 127 Example 22 4’-[(2-Phenyl-benzimidazol-l-yl)-methyl]biphenyl-2carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-phenyl-benzimidazol-l-yl)-methyl)biphenyl-2 -carboxylate and trifluoroacetic acid.
Yield: 56.8 % of theoretical, Melting point: 275-277 °C C27H20N2O2 (404.47) Calculated: C 80.18 H 4.98 N 6.93 Found: 79.90 5.05 6.92 Example 23 4(2-(Thiazol-4-yl)-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4·-[(2-(thiazol-4-yl)-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid. Yield: 94.6 % of theoretical; Melting point: 284-286 °C C24H17N3O2S (411.48) Calculated: C 70.06 H 4.16 N 10.21 S 7.79 Found: 69.90 4.29 9.97 7.59 Example 24 4(2-(3,5-Dimethyl-pyrazol-l-yl)-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4·-((2-(3,5-dimethyl-pyrazol-l-yl)-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and 128 trifluoroacetic acid.
Yield: 87.2 % of theoretical, Melting point: 185-187 °C C26H22NaO2 (422.49) Calculated: C 73.92 H 5.25 N 13.26 Found: 73.86 5.37 13.27 Example 25 ’ — [ (2— (Fur-2-yl)-benzimidazol-l-yl) -methyl]biphenyl-2 carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4‘-[(2-(fur-2-yl)-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 78.4 % of theoretical.
Melting point: 263-265 °C C25Hi8N2O3 (394.43) Calculated: 0 76.13 H 4.60 N 7.10 Found: 75.94 4.64 6.83 Example 26 · — [ (2-Aminocarbonylamino-benzimidazol-l-yl) -methyl ] biphenyl-2-carboxylic acid monohydrate Prepared in analogous manner to Example 9 from tert.butyl 4’-((2-aminocarbonylamino-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid. Yield: 53.3 % of theoretical, Melting point: 214-216 °C C22H18N,O3 X H2O (404.42) Calculated: C 65.34 H 4.98 N 13.85 Found: 65.18 5.05 13.61 129 Example 27 ’-[(2-Isopropyl-benzimidazol-l-yl)-methyl]biphenyl-2carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4(2-isopropyl-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 80 % of theoretical, Melting point: 206-208 °C WWl (370.46) Calculated: C 77.81 H 5.99 N 7.56 Found: 77.55 5.97 7.43 Example 28 ’ -[(7-Benzyloxy-2-n-butyl-4-methyl-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid trifluoroacetate Prepared in analogous manner to Example 9 from tert.butyl 4'-[(7-benzyloxy-2-n-butyl-4-methyl-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 85.5 % of theoretical, Melting point: 217-219 °C Cd3H32N2O3 X CF3COOH (618.66) Calculated: C 67.95 H 5.37 N 4.52 Found: 68.19 5.56 4.74 Example 29 4·-[(2-Hydroxymethyl-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid trifluoroacetate Prepared in analogous manner to Example 9 from tert.butyl 4*-[(2-hydroxymethyl-benzimidazol-l-yl)130 methyl]biphenyl-2-carboxylate and trifluoroacetic acid. Yield: 81.9 % of theoretical, Melting point: 188-190 °C C22H18N2O3 X CF3COOH (472.42) Calculated: C 61.02 H 4.05 N 5.93 Found: 61.23 4.08 5.91 Example 30 4'-((2-(3-Hydroxypropyl-benzimidazol-l-yl)-methyl) bipheny1-2-carboxylic acid trifluoroacetate Prepared in analogous manner to Example 9 from tert.butyl 41-[(2-(3-hydroxypropyl-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid. Yield: 58.8 % of theoretical, Melting point: 150^-152 °C C222N2O3 X CF3COOH (500.47) Calculated: C 62.40 H 4.63 N 5.60 Found: 62.13 4.70 5.83 Example 31 4'-[(2-Methyl-5-and 6-(N-(2-methoxyacetyl)-nbutylamino)-benzimidazol-l-ylj-methyl]biphenyl-2carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4 ’ - [ (2-methyl-5-and 6-(N-(2-methoxyacetyl,-n butylamino) -benzimidazol-l-yl) -methyl) biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 84.8 % of theoretical.
Melting point: 186-188 °C C29H31N3Oa (485.58) Calculated: C 71.73 H 6.43 N 8.65 Found: 72.67 6.68 8.74 131 Example 32 · - ((2-(1-Methylpropyl)-benz imidazol-l-yl)-methyl]biphen yl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4(2-(l-methylpropyl)-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
]Q Yield: 80 % of theoretical, Melting point: 147-148 °C C25H2AN2O2 (384.48) Calculated: C 78.10 H 6.29 N 7.29 Found: 77.91 6.23 7.37 Example 33 ’ -[(2-(2-Methylbutyl)-benz imidazol-l-yl)-methyl]bipheny 1-2-carboxylic acid ---;-:-:Prepared in analogous manner to Example 9 from tert.butyl 4(2-(2-methylbutyl)-benzimidazol-l-yl)methyl)biphenyi-2-carboxylate and trifluoroacetic acid. Yield: 60 % of theoretical, 25 Melting point: 209-210 °C C26H28N2O2 (398.51) Calculated: C 78.36 H 6.58 N 7.03 Found: 78.27 6.51 6.99 3Q Example 34 · — [(2-Methyl-5-and 6-(N-(2-methoxyethyl)-n-butylamino)-benzimidazol-l-yl)-methyl]bipheny1-2-carboxylic acid -:Prepared in analogous manner to Example 9 from tert.butyl 4’-[(2-methyl-5-and 6-(N-(2-methoxyethyl)-n132 butylamino)-benzimidazol-l-yl)-methyl]biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 46.5 % of theoretical.
Melting point: 102-106 °C C29H33N3O3 (471.598) Calculated: C 73.86 H 7.05 M 8.91 Found: 73.60 7.13 8.85 Example 35 4'-[(2-n-Pentyl-benzimidazol-l-yl)-methyl]biphenyl-2carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'(2-n-pentyl-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 87 % of theoretical,..
Melting point: 181-183 °C C26H26N2O2 (398.51) Calculated: C 78.36 H 6.58 N 7.03 Found: 78.12 6.42 7.09 Example 36 4'-((Benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-[(benzimidazol-l-yl)-methyl]biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 90.9 % of theoretical, Melting point: 217-219 °C C21H10N2O2 (328.37) Calculated: C 76.81 H 4.91 N 8.53 Found: 77.03 5.00 8.42 133 Example 37 (2-n-Butyl-4-methyl-7-methoxy-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-4-methyl-7-methoxy-benzimidazol-l-y1)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 86.6 % of theoretical, Melting point: 216-218 °C C27H28N2O3 (428.54) Calculated: C 75.68 H 6.59 N 6.54 Found: 75.48 6.59 6.45 Example 38 4’—[(2-n-Propyl-benzimidazol-l-yl)-methyl]biphenyl-2carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4·—[(2-n-propyl-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 85.2 % of theoretical.
Melting point: 237-238 °C C24H22N2O2 (370.45) Calculated: C 77.81 H 5.99 N 7.56 Found: 78.08 5.74 7.37 134 Example 39 4' — [ (2-Ethyl-benzimidazol-l-yl) -methyl]biphenyl-2carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4 ’ - [ (2-ethy 1-benz imidazol-l-yl) -methyl ]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 81.6 % of theoretical, Melting point: 251-253 °C C23H20N2O2 (356.42) Calculated: C 77.51 H 5.66 M 7.86 Pound: 77.72 5.64 7.59 Example 40 * — [ (2-Ethylthiomethyl-benzimidazol-l-yl) -methyl]biphenyl-2 -carboxylic acid semi-trifluoroacetate Prepared in analogous manner to Example 9 from tert. butyl 4' - [ (2-ethylthiomethyl-benzimidazol-l-yl) methyl]biphenyl-2-carboxylate and trifluoroacetic acid. Yield: 96.1 % of theoretical, Melting point: 139-141 °C C2aH22N2O2S x 1/2 CF3COOH (459.52) Calculated: C 65.35 H 4.94 N 6.10 S 6.98 Found: 65.24 5.00 6.18 6.98 Example 41 4(2-Methylthiomethyl-benzimidazol-l-yl) -methyl]bipheny 1-2-carboxylic acid semi-trifluoroacetate Prepared in analogous manner to Example 9 from 135 tert.butyl 4’-[(2-methylthiomethyl-benzimidazol-i-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid. Yield: 98.6 % of theoretical, Melting point: 147-149 °C C23H20N2O2S X 1/2 CF3COOH (445.495) Calculated: C 64.71 H 4.64 N 6.29 S 7.20 Found: 64.70 5.04 6.51 6.91 Example 42 4(2-Chloro-benzimidazol-l-yl)-methyl]biphenyl-2carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-chloro-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 84.0 % of theoretical, Melting point: 169-171 °C C21H15C1N2O2 (362.815) Calculated: C 69.52 H 4.17 N 7.72 Cl 9.77 Found: 69.39 4.13 7.66 9.72 Example 43 4' - [ (2-n-Butylthio-benzimidazol-l-yl) -methyl ] biphenyl-2carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4·-[(2-n-butylthio-benzimidazol-l-yl)methyl)biphenyl-2-carboxylate and trifluoroacetic acid. Yield: 88.0 % of theoretical.
Melting point: 160-162 °C C25H24N2O2S (416.54) Calculated: C 72.09 H 5.81 N 6.73 Found: 71.93 5.75 6.74 S 7.70 7.71 136 Example 44 4'-((2-n-Butyl-5-acetamino-benzimidazol-l-yl) -methyl) bipheny1-2-carboxylicacid hydrate Prepared in analogous manner to Example 9 from tert. butyl 41 - [ (2-n-butyl-5-acetamino-benzimidazol-lyl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 71.3 % of theoretical.
Melting point: 187-189 °C C27H27N3O3 X H2O (459.54) Calculated: C 70.56 H 6.36 N 9.14 Found: 70.40 6.22 9.08 Example 45 · -[ (2— (4-Methoxyphenyl) -benzimidazol-l-yl) -methyl]biphe nyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4*-[(2-(4-methoxypheny!)-benzimidazol-l-yl)methyl]bipheny1-2-carboxylate and trifluoroacetic acid. Yield: 87.5 % of theoretical, Melting point: 283-286 °C C2eH22N2O3 (434.50) Calculated: C 77.40 H 5.10 N 6.45 Found: 77.45 5.20 6.44 Example 46 * - [ (2-n-Propylthio-benzimidazol-l-yl) -methyl]biphenyl2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-propylthio-benz imidazol-l-yl)137 methyl]biphenyl-2-carboxylate Yield: 90.5 % of theoretical, Melting point: 219-220 °C C24H22N2O2S (402.51) Calculated: C 71.62 H Found: 71.47 and trifluoroacetic acid. .51 N 6.96 S 7.97 5.51 6.75 8.09 Example 47 ’ — [ (2-n-Butylamino-benzimidazol-l-yl) -methyl ]biphenyl2-carboxylic acid semi-trifluoroacetate Prepared in analogous manner to Example 9 from tert.butyl 4'(2-n-butylamino-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid. Yield: 80.0 % of theoretical.
Melting point: 247-249 °C C25H25N3O2 x 1/2 CF3COOH (456.50) Calculated: C 68.41 H 5.63 N 9.20 Found: 68.56 5.84 9.07 Example 48 ’ (2-(4-Methoxyphenyl)-5-and 6-chloro-benzimidazol-lyl)-methyl] biphenyl-2-carboxy lie acid Prepared in analogous manner to Example 9 from tert.butyl 4'-((2-(4-methoxyphenyl)-5-and 6-chlorobenzimidazol-l-yl) -methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 76.3 % of theoretical, Melting point: 234-236 °C C28H21C1N2O3 (468.95) Calculated: C 71.71 H 4.51 N 5.97 Cl 7.56 Found: 71.57 4.39 5.85 7.79 138 Example 49 * - [(2-n-Butyl-5-methoxy-benzimidazol-l-yl)-methyl]bi phenyl-2-carboxylicacid Prepared in analogous manner to Example 9 from tert.butyl 4 *-[(2-n-butyl-5-methoxy-benz imidazol-l-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid. Yield: 66.2 % of theoretical, Melting point: 203-205 °C C26H26N2O3 (414.51) Calculated: C 75.34 H 6.32 N 6.76 Found: 75.19 6.31 6.61 Example 50 4·-[(2-n-Butyl-5-and 6-acetamino-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to. Example 9 from tert.butyl 41-[(2-h-butyl-5-and 6-acetamino-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 83.7 % of theoretical, Melting point: 117-119 °C C27H27N3O3 (441.54) Calculated: C 73.45 H 6.16 N 9.52 Found: 73.25 6.23 9.47 Example 51 * —((2-n—Butyl—5—and 6-butanoylamino-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4·-[(2-n-buty1-5-and 6-butanoylamino139 benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 80.0 % of theoretical, Melting point: 123-127 °C C2gH31N3O3 (469.59) Calculated: C 74.18 H 6.65 N 8.95 Found: 73.96 6.19 8.99 Example 52 4’—[(6— (N-Benzyl-methylamino) -2-n-butyl-benzimidazol-lyl)-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4’(6-(N-benzyl-methylamino)-2-n-butylbenzimidazol-l-yl) -methyl] biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 82.0 % of theoretical.
Melting point: 237-238 °C C33H33N3O2 (503.64) Calculated: C 78.70 H 6.60 N 8.34 Found: 78.68 6.71 8.44 Example 53 *-[(2-n-Butyl-5-chloro-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4·-[(2-n-butyl-5-chloro-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid. Yield: 70.6 % of theoretical, Melting point: 191-193 °C C25H23C1N2O2 (418.92) Calculated: C 71.68 H 5.53 N 6.69 Cl 8.46 Found: 71.48 5.40 6.53 8.43 140 Example 54 4·-[(2-n-Butyl-5-and 6-methoxy-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-5-and 6-methoxy-benzimid-azol1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 84.1 % of theoretical, Melting point: 128-133 °C C26H26N2O3 (414.51) Calculated: C 75.34 H 6.32 N 6.76 Found: 75.32 6,14 6.75 Example 55 4’-[(2-n-Butyl-7-n-butoxy-4-methyl-benzimidazol-l-yl)methyl]biphenyl-2-carboxylicacid trifluoroacetate Prepared in analogous manner to Example 9 from tert.butyl 4(2-n-butyl-7-n-butoxy-4-methylbenzimidazol-l-yl)-methyl]biphenyl-2-carboxylate in methylene chloride.
Yield: 63.3 % of theoretical, Melting point: 172-173 °C C30H„N2O3 x CF3COOH (584.65) Calculated: C 65.74 H 6.03 N 4.73 Found: 66.52 6.15 4.95 141 Example 56 2-n-Butyl-l-[(2-carboxy-biphenyl-4'-yl)methyl]-6,7dihydro-7,7-dimethyl-5-ethyl-5H-pyrrolo[2,3-f]benzimidazol-6-one semi-hydrate g (10.3 mmol) of 6-amino-5-[(2-tert.butoxycarbonyl-biphenyl-4 '-yl)-methyl]-amino-3,4-dimethyl-l-ethyl-indol2-one and 5 ml of valeric acid are heated at reflux for 4 hours. After cooling, the mixture is stirred into 50 ml of saturated aqueous sodium carbonate solution. It is extracted by shaking 3 times using 30 ml of methylene chloride each time. The methylene chloride phase is dried using sodium sulphate and evaporated in vacuum.
The crude product is purified using a silica gel column (eluting agent: ethyl acetate/ethanol/ammonia = 90:10:1).
Yield: 1.55 g (30.3 % of theoretical), Melting point: 185-187 °C C31H33N3O3 X 1/2 H2O (504.64) Calculated: C 73.81 H 6.79 N 8.33 Found: 73.91 6.86 8.36 Example 57 *-[ (2-n-Butyl-7-hydroxy-4-methyl-benzimidazol-l-yl) imethyl]-2-(lH-tetrazol-5-yl)-biphenyl hydrate 0.9 g (1.7 mmol) of 4»-[(2-n-butyl-7-benzyloxy-4-methylbenzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)biphenyl, dissolved in 100 ml of methanol, are hydrogenated at ambient temperature at 5 bar hydrogen pressure in the presence of 0.9 g of 20 % palladium hydroxide dn carbon. The catalyst is then filtered off under suction and the filtrate is evaporated to dryness 142 in vacuum. The crude product is recrystallised from acetone/ether and dried at 50 °C in vacuum.
Yield: 0.72 g (97.3 % of theoretical), Melting point: 231-233 °C C26H26N6O X H20 ( 456.56) Calculated: C 68.40 H 6.18 N 18.40 Found: -68.64 6.40 18.55 The following compounds are obtained in analogous manner: 41 — [(2-n-butyl-7-hydroxy-4-methyl-benzimidazol-l-yl)methyl]-2-trifluoroacetamino-biphenyl melting point: 243-245 °C 4'-[(2-n-butyl-7-hydroxy-4-methyl-benzimidazol-l-yl)methyl]-2-trifluoromethanesulphonamino-biphenyl melting point: 160-162 °C tert.butyl 4·-[(2-n-butyl-7-hydroxy-benzimidazol-l-yl)methyl)bipheny1-2-carboxylate oil, Rf value: 0.60 (Silica gel: methylethylketone/xylene = 1:1) tert.butyl 4' - [(2-n-buty1-6-hydroxy-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate oil, Rf value: 0.55 (Silica gel: methylethylketone/xylene = 1:1) tert.butyl 4'-[(2-n-butyl-4-hydrOxy-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate melting point: 91-93 °C tert.butyl 41-((2-n-butyl-5-hydroxy-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate oil, Rf value: 0.60 (Silica gel: methylethylketone/xylene = 1:2) 143 4'-[(2-n-butyl-7-hydroxy-4-methyl-benzimidazol-l-yl)methyl]-2-phthalimino-biphenyl melting point: 224-226 °C Example 58 *-[(2-n-Butyl-benz imidazol-l-yl)-methyl]-2-(1Htetrazol-5-yl)-biphenyl a) 4'-[(2-n-Butyl-benzimidazol-l-yl)-methyl]-2-(1triphenvlmethvltetrazol-5-vl)-biphenyl 0.87 g (5 mmol) of 2-n-butyl-benzimidazole is dissolved in 20 ml of dimethylsulphoxide and 0.61 g (5.5 mmol) of potassium tert.butoxide is added with stirring. After 1/2 hour, 4 ·-bromomethyl-2-(1-triphenylmethyl-lHtetrazol-5-yl)-biphenyl is added and the mixture is stirred for 3 hours at ambient temperature. It is poured into about 50 ml of iced water and extracted by shaking 3 times using 30 ml of ethyl acetate each time. The ethyl acetate phase is extracted by shaking using 20 ml of water, dried over sodium sulphate and evaporated to dryness. The crude product is purified Over a silica gel column (grain size: 0.063-0.2 mm, eluting agent: methylene chloride/ethanol = 100:1).
Yield: 2.1 g (64.6 % of theoretical), Melting point: 85-87 °C C„H38N6 (650.84) Calculated: C 81.20 H 5.88 N 12.91 Found: 80.97 5;90 12.66 b) 4'-[(2-n-Butyl-benzimidazol-l-yl)-methyl]-2-(1Htetrazol-5-νί)-biphenyl g (3 mmol) of 41-[(2-n-butyl-benzimidazol-l-yl)methyl]-2-(l-triphenylmethyl-tetrazol-5-yl)-biphenyl are 144 dissolved in a mixture of 10 ml of methylene chloride and 10 ml of methanol, treated with 10 ml of etherified hydrochloric acid and stirred at ambient temperature for 3 hours. The mixture is rotary evaporated to dryness in vacuum. The residue is dissolved in methanol, rendered'alkaline using ammonia and rotary evaporated once again. The exude product is purified over a silica gel column (grain size: 0.063-0.2 mm, eluting agent: methylene chloride/ethanol/ammonia == 19:1:0.1). The product is crystallised from ether and dried at 50 °C in vacuum.
Yield: 1.02 g (81.6 % of theoretical), Melting point: 241-243 °C C25H24N6 (408.52) Calculated: C 73.50 H 5.92 N 20.57 Found: 73.34 5.92 20.47 Example 59 ’-[ (2-n-Butyl-7-benzyloxy-4-methyl-benzimidazol-l-yl) methyl ] -2- (lH-tetrazol-5-yl) -biphenyl semi-hydrate A mixture of 3.8 g (7.1 mmol) of ammonium chloride, 4.5 g (69 mmol) of sodium azide, 20 ml of dimethylformamide and 2.2 g (4.53 mmol) of 4*-[(2-n-hutyl-7-benzyloxy-4methyl-benzimidazol-l-yl) -methyl) -2-cyano-biphenyl is heated at 120 °C internal temperature for 36 hours with stirring. The sodium chloride formed is filtered off and the filtrate is rotary evaporated in vacuum. 50 ml of water are added to the oily residue and the solution is adjusted to pH 2 using concentrated hydrochloric acid with cooling. The oily crude product is filtered off, taken up in 50 ml of methylene chloride and dried over sodium sulphate. It is then purified over a silica gel column (grain size 0.063-0.2 mm, eluting agent: methylene chloride/ethanol = 19:1). The homogeneous 145 fractions are evaporated to dryness in vacuum and the residue is dried at 50 °C.
Yield: 1.6 g (68 % of theoretical), Melting point: 112-116 °C C33H32N6O X 1/2 H2O (537.66) Calculated: C 73.73 H 6.18 N 15.63 Found: 73.55 6.33 15.91 Example 60 4(7-Acetoxy-2-n-butyl-4-methyl-benzimidazol-l-yl)methyl]bipheny1-2-carboxylic acid 0.55 g (1 mmol) of 4·-[(2-n-butyl-7-hydroxy-4-methylbenzimidazol-l-yl)-methylJbiphenyl-2-carboxylic acid trifluoroacetate is dissolved in 20 ml of pyridine. 0.5 ml (7 mmol) of acetyl chloride is added dropwise to the mixture at 5 °C with stirring. The mixture is stirred for 1 hour at 5 °C and then for 2 hours at ambient temperature. The pyridine is distilled off in vacuum on a rotary evaporator. The residue is mixed with water and filtered under suction. After washing with water, it is dried at 50 °C in vacuum.
Yield: 0.43 g (94 % of theoretical), Melting point: 242-244 °C C28H28N2OA (456.55) Calculated: C 73.66 H 6.18 N 6.14 _ Found: 73.50 6.20 6.36 u Example 61 4' — [(7-n-Butoxy-2-n-butyl-4-methyl-benzimidazol-l-yl),. methyl]bipheny 1-2-carboxylic acid trifluoroacetate 146 a) Tert.butyl 4'-[(7-n-butoxy-2-n-buty1-4-methylbenzimidazol-l-vl)-methyl!biphenyl-2-carboxylate A mixture of 0.94 g (2 mmol) of tert.butyl 4’-[(2-nbuty1-7-hydroxy-4-methy1-benzimidazol-l-yl)methyl)biphenyl-2-carboxylate, 36 ml of dimethyl formamide, 4 ml of water, 1.4 g (10 mmol) of potassium carbonate and 0.9 g (6.6 mmol) of nbutylbromide is stirred for 16 hours at ambient temperature. The mixture is poured onto 200 ml of iced water and the oily precipitate obtained is taken up in methylene chloride after being decanted off. The methylene chloride solution is dried over sodium sulphate and evaporated in vacuum. The crude product is purified over a silica gel column (grain size: 0.065-0.2 mm, eluting agent: methylene chloride/ethanol = 50:1). Yield: 0.8 g (76.2 % of theoretical), oil, Rf value: 0.6 (Silica gel: methylene chloride/ethanol = 19:1) C3«H42N2O3 (526.7) Calculated: C 77.53 H 8.04 N 5.32 Found: 77.53 7.87 5.31 The following compounds are obtained in analogous manner: tert. butyl 4·-[(2-n-butyl-7-methoxy-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate oil, Rf value: 0.70 (Silica gel: methylethylketone/xylene = 1:1) tert.butyl 4'-[(2-n-buty1-7-(2-methoxyethoxy)-4-methylbenz imidazol-l-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.35 (Aluminium oxide plate: methylene chloride/ethanol = 99:1) 147 b) 4*-[ (7-n-Butoxy-2-n-butyl-4-methyl-benzimidazol-lyl)-methyl]biphenyl-2-carboxylic acid trifluoroacetate 0.8g (1.5 mmol) of tert.butyl 4'-[(7-n-butoxy-2-nbutyl-4-methyl-benzimidazol-l-yl)-methyl]biphenyl-2carboxylate are dissolved in 15 ml of methylene chloride, 5 ml of trifluoroacetic acid are added and the mixture is stirred for 2 hours at ambient temperature. The product is rotary evaporated to dryness in vacuum and the residue is recrystallised from acetone. The crystals are dried at 50 °C in vacuum.
Yield: 0.45 g (51.3 % of theoretical).
Melting point: 172-174 °C C30H3AN2O3 X CF3COOH (584.65) I b Calculated: C 65.74 H 6.03 N 4.73 Found: 65.52 6.15 4.95 The following compounds are obtained in analogous manner: 4'-[ (2-n-butyl-7-(2·?(1-imidazolyl)-ethoxy)-4-methylbenzimidazol-l-yl) -methyl]biphenyl-2-carboxylic acid bis-trifluoroacetate melting point: 229-231 °C 4'-[(2-n-butyl-7-(2-hydroxyethoxy)-4-methylbenzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid melting point: 216 °C Example 62 ’-[(2-n-Butyl-4-hydroxy-7-methyl-benzimidazol-l-yl)methyl)biphenyl-2-carboxylic acid 35 Prepared in analogous manner to Example 57 from 4’-[(4148 benzyloxy-2-n-butyl-7-methyl-benzimidazol-l-y 1) methyl]biphenyl-2-carboxylic acid and hydrogen in methanol/dimethylformamide in the presence of 20 % palladium hydroxide on carbon.
Yield: 64.4 % of theoretical, Melting point: 291-294 °C C26H26N2O3 (414.51) Calculated: C 75.34 H 6.32 N 6.76 Found: 75.22 6.40 6.64 Example 63 ' — [ (2-Ethylsulphiny lmethyl-benzimidazol-l-yl) methyl)biphenyl-2-carboxylie acid 2.01 g (5.0 mmol) of 4(2-ethylthiomethy1-benzimidazol-l-yl) -methyl]biphenyl-2~carboxylic acid are dissolved in 25 ml of glacial acetic acid and treated with 0.51 ml of-30 % strength hydrogen peroxide. The solution is allowed to stand for 24 hours at ambient temperature and is then evaporated to dryness. The residue is purified over a silica gel column (grain size: 40-63 gm, eluting agent: methylene chloride/ethanol/glacial acetic acid = 50/1/0.15). The homogeneous fractions are combined, the solvents are distilled off, the residue is dissolved in methylene chloride and washed three times using water.The organic phase is dried using magnesium sulphate and evaporated to dryness. The crystalline residue is mixed with diethylether, the mixture is filtered under suction and the crystals are dried at 75 °C in vacuum.
Yield: 1.90 g (90.9 % of theoretical), Melting point: 161-163 °C C«H22N2O3S (418.51) Calculated: C 68.88 H 5.30 N 6.69 S 7.66 Found: 68.65 5.40 6.72 7.64 149 Example 64 · — [ (2-n-Propylsulphinylmethyl-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 63 from 4*-[(2n-propylthiomethyl-benzimidazol-l-yl)-methyl]-biphenyl2-carboxylic acid and hydrogen peroxide in glacial acetic acid.
Yield: 78.7 % of theoretical, Melting point: 128-130 °C C25H2AN2O3S (432.54) Calculated: C 69.42 H 5.59 N 6.48 S 7.41 Found: 69.57 5.46 6.04 7.28 Example 65 ·-[ (2-Hydroxy-benzimidazol-l-yl) -methyljbipheny 1-2carboxy lie acid 3-N-oxide Prepared in analogous manner to Example 63 from 4*-[(2methylmercapto-benzimidazol-l-yl)-methyl]biphenyl-2carboxylic acid and hydrogen peroxide in glacial acetic acid.
Yield: 35.9 % of theoretical, Melting point: 272-274 °C C21H16N2O, (360.37) Calculated: C 69.99 H 4.47 N 7.77 Found: 70.00 4.85 7.51 150 Example 66 4(2-Methylsulphinylmethyl-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 63 from 4·-[(2methylthiomethyl -benzimidazol-l-yl) -methyl ] biphenyl-2carboxylic acid and hydrogen peroxide/acetic acid. Yield: 79.2 % of theoretical.
Melting point: 232-234 °C C23H20N2O3S (404.48) Calculated: C 68.30 H 4.98 N 6.93 S 7.93 Found: 68.17 4.86 7.04 7.89 Example 67 4' - [ (2-Ethylsulphonylmethyl-benzimidazol-l-yl) -methyl ] biphenyl-2-carboxylic acid 2.01 g (5.0 mmol) of 4·-[ (2-ethylthiomethyl-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid are dissolved in 25 ml of formic acid and 1.02 ml (10 mmol) of 30 % strength hydrogen peroxide are added. The solution is allowed to stand at ambient temperature for 24 hours and is then evaporatedtodryness.The residue is purified over a silica gel column (grain size: 40-63 gm, eluting agent: methylene chloride/ethanol/glacial acetic acid = 100/1/0.15 to 50/1/0.15). The homogeneous fractions are combined and evaporated to dryness. The residue is dissolved in methylene chloride, washed three times using water, the organic phase is dried using magnesium sulphate and evaporated to dryness. The crystalline residue is mixed with diethylether, filtered under suction and dried at 75 °C in vacuum. Yield: 1.80 g (82.9 % of theoretical), Melting point: 158-160 °C C„H22N2O 151 Calculated: Found: C 66.34 66.32 H 5.10 5.05 N 6.45 6.54 S 7.38 7.27 The following compounds are obtained in analogous manner: 4(2-n-butyl-6-methylsulphonyl-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid 4·-[(2-n-butyl-6-ethylsulphonyl-benzimidazol-l-yl)methyl]bipheny1-2-carboxylic acid * -[(2-n-butyl-6-n-butylsulphonyl-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid Example 68 ’ — [(2-n-Propylsulphonylmethyl-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 67 from 4’-[(2n-propylthiomethy.l-benz imidazol-l-yl) -methyl ]biphenyl-2carboxylic acid and hydrogen peroxide in formic acid. Yield: 78.1 % of theoretical, Melting point: 135-137 °C C25H24N2O4S (448.54) Calculated: C 66.95 H 5.39 N 6.25 S 7.15 Found: 66.83 5.46 6.03 7.06 Example 69 · - [ (2-Methylsulphonylmethyl-benzimidazol-l-yl) methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 67 from 4’-[(2methylthiomethyl-benzimidazol-l-yl)-methyl]biphenyl-2152 carboxylic acid and hydrogen peroxide.
Yield: 80.0 % of theoretical, Melting point: 290-292 °C C23H20N2O4S (420.48) Calculated: C 65.70 H 4.79 N 6.66 S 7.62 Found: 65.67 4.64 6.88 7.72 Example 70 jq Ethyl 4'-[ (2-n-butyl-benzimidazol-l-yl) -methyl]biphenyl2-carboxylate 1.2 g (7 mmol) of 2-n-butyl-benzimidazole are dissolved in 25 ml of dimethylsulphoxide, treated with 0.8 g (7 mmol) of potassium tert.butoxide and the mixture is stirred for 20 minutes at ambient temperature. 2.25 g (7 mmol) of 2-carbethoxy-biphenyl-4 ‘-yl-methylbromide are then added and the mixture is stirred at ambient temperature until conversion is quantitative (about 1 hour). After pouring into 100 ml of iced water, the product is extracted 2 times using ethyl acetate, the combined organic extracts are dried over sodium sulphate and evaporated. The exude product obtained is purified over a silica gel column (grain size: 0.06-0.2 mm, eluting agent: methylene chloride/ethanol = 24:1).
Yield: 2.3 g (79.3 % of theoretical).
Oil, Rf value: 0.6 (Silica gel: methylethylketone/xylene = 1:1) C27H28N2O2 (412.53) Calculated: C 78.61 H 6.84 N 6.79 Found: 78.43 6.76 7.01 The following compound is obtained in analogous manner: ethyl 4'-[(2-n-butyl-7-n-butylsulphonamino-benzimidazoll-yl )-methyl]bipheny1-2-carboxylate oil, Rf value: 0.50 (Silica gel: methylene 153 chloride/ethanol = 10:1) Example 71 ' -[ (2-n-Butyl-benzimidazol-l-yl) -methyl]biphenyl-2carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 62.3 % of theoretical, Melting point: 214-215 °C C25H„N2O2 (384.48) Calculated: C 78.10 H 6.29 N 7.29 Found: 77.93 6.21 7.39 Example 72 ' -[ (6-Benzylamiri0-2-n-butyl-benzimidazol-l-yl) methyl]biphenyl-2-carboxylic acid 1.30 g (2.5 mmol) of ethyl 4*-[(6-benzylamino-2-nbutylbenz imidazol-l-yl) -methyl ] biphenyl-2-carboxylate are dissolved in 20 ml of ethanol, treated with 20 ml of 2N sodium hydroxide and heated at reflux for 2 hours. After cooling to ambient temperature, the solution is diluted to 500 ml using water and acidified to pH 5 using glacial acetic acid. The precipitate thus obtained is filtered off under suction, suspended in acetone, filtered off once again under suction and dried at 90 °C in vacuum.
Yield: 1.10 g (89.4 % of theoretical), Melting point: 250-251 °C C32H31N3O2 (489.62) Calculated: C 78.50 H 6.38 N 8.58 Found: 78.30 6.49 8.71 154 The following compound is obtained in analogous manner: (2-n-butyl-7-cyclohexylaminocarbonylaminobenzimidazol-l-yl)-methyljbiphenyl-2-carboxylic acid melting point: 278-279 °C (decomposition) Example 73 ’-[ (2-n-Butyl-4-methyl-7-hydroxy-benzimidazol-l-yl) methyl]biphenyl-2-carboxylic acid hydrate Prepared in analogous manner to Example 72 from methyl 4 * — [(2-n-butyl-4-methyl-7-hydroxy-benzimidazol-l-yl)methyljbiphenyl-2-carboxylate and 2N sodium hydroxide in ethanol.
Yield: 55.1 % of theoretical, Melting point: 313-315 °C C26H26N2O3 X H2O (432.52) Calculated: C 72.20 H 6.53 N 6.43 Found: 72.43 6.30 6.34 Example 74 Tert.butyl 4'-[(2-n-buty1-4-methy1-7-hydroxybenzimidazol-l-yl)-methyl]biphenyl-2-carboxylate Prepared in analogous manner to Example 57 from tert.butyl 4‘-[(2-n-butyl-4-methyl-7-benzyloxybenzimidazol-l-yl) -methyl]biphenyl-2-carboxylate and hydrogen in the presence of palladium hydroxide on carbon in methanol.
Yield: 80.0 % of theoretical, Melting point: 214-216 °C C30H3aN2O3 (470.62) 155 Calculated: Found: C 76.57 76.83 H 7.28 7.12 N 5.95 6.00 Example 75 · — [ (2-n-Butyl-7-methyl-benzimidazol-l-yl) -methyl]biphenyl-2-carboxylic acid hydrate Prepared in analogous manner to Example 56 from 3-amino2—[(2-tert.butoxycarbonyl-biphenyl-4‘-yl)methyl]aminotoluene and valeric acid.
Yield: 28.6 % of theoretical, Melting point: 231-233 °C C26H26N2O2 X H2O (416.52) Calculated: C 74.98 H 6.78 N 6.73 Found: 74.89 6.52 6.85 Example 76 ' — [ (6—Amino—2—n—butyl—benz imidazol—1—yl) —methyl ]biphenyl-2-carboxylic acid ditrifluoroacetate Prepared in analogous manner to Example 9 from tert.butyl 4'-[(6-eunino-2-n-butyl-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid. Yield: 72.5 % of theoretical, Melting point: 72-74 °C C25H25N3O2 X 2 CFgCOOH (627.54) Calculated: C 55.51 H 4.34 N 6.70 Found: 55.70 4.61 6.55 Example 77 4’-[(5-Amino-2-n-buty1-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid ditrifluoroacetate 156 Prepared in analogous manner to Example 9 from tert.butyl 4 · -[(5-amino-2-n-butyl-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid. Yield: 45.9 % of theoretical, Melting point: 64-66 °C C25H25N3O2 X 2 CF3COOH (627.54) Calculated: C 55.51 H 4.34 N 6.70 Found: 55.66 4.42 6.54 Example 78 ’ — [(2-n-Butyl-5-(n-butylaminocarbonylamino)-benzimidazo 1-1-yl)-methyl]biphenyl-2-carboxylic acid semitr i fluoroacetate Prepared in analogous manner to Example 9 from tert.butyl 4·-[(2-n-butyl-5-(n-butylaminocarbonylamino)benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 84.2 % of theoretical, Melting point: 165-167 °C C3PH34N4O3 X 1/2 CF3COOH (555.64) Calculated: C 67.01 H 6.26 N 10.08 Found: 66.88 6.51 9.89 Example 79 4·—[(2—n—Butyl—6—phenylaminocarbonylamino—benzimidazoll-yl) ~methyl]biphenyl—2—carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4·-[(2-n-butyl-6-phenylaminocarbonylaminobenzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 92.6 % of theoretical, Melting point: 281-283 °C 157 C32H30N«O3 (518.61) Calculated: C 74.11 H 5.83 N 10.80 Found: 73.93 5.83 10.58 Example 80 * - [(2-n-Butyl-6-cyclohexylaminocarbonylaminobenzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid tri fluoroacetate Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-cyclohexylaminocarbonylamino-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 86.5 % of theoretical, Melting point: 199-200 °C C32H36NAO3 X CF3COOH (638.68) Calculated: C 63.94 H 5.84 N 8.77 Found: 64.12 6.15 9.01 Example 81 ’ —[(2-n-Butyl-5-butanoylamino-benzimidazol-l-yl)methyl]biphenyl-2-carboxyiic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-5-butanoylamino-benziffiidazol1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Yield: 93 % of theoretical, Melting point: 163-165 °C C29H31N3O3 (469.59) Calculated: C 74.18 H 6.65 N 8.95 Found: 74.13 6.67 8.74 Example 82 158 *-[(2-(4-Hydroxyphenyl)-benzimidazol-l-yl)-methyljbiphe nyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4·-[(2-(4-hydroxyphenyl)-benzimidazol-l-yl)methyl]bipheny1-2-carboxylate and trifluoroacetic acid/methylene chloride.
Yield: 87.3 % of theoretical, Melting point: 251-253 °C C27H2oN203 (420.47) Calculated: C 77.13 H 4.79 N 6.66 Found: 76.98 4.83 6.62 Example 83 *-[(2—(4—n-Butoxyphenyl)-benzimidazol-l-yl)-methyl]biph eny1-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4*-[(2-(4-n-butoxyphenyl)-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Yield: 85.2 % of theoretical, Melting point: 246-248 °C C3iH2eN2O3 (476.58) Calculated: C 78.13 H 5.92 N 5.88 Found: 78.33 5.76 5.67 Example 84 4·-[(2-n-Butyl-6-chloro-benzimidazol-l-yl)-methyljbiphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-chloro-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic 159 acid/methylene chloride.
Yield: 63.6 % of theoretical, Melting point: 220-222 °C C25H23C1N2O2 (418.92) Calculated: C 71.68 H 5.53 -N 6.69 Cl Found: 71.81 5.64 6.69 8.46 8.39 160 Example 85 · — [(2-n-Butyl-6-methyl-benzimidazol-l-yl)-methyl]bipheny1-2-carboxylic acid Prepared in analogous manner to Example 9 from tert .butyl 4 · - [ (2-n-butyl-6-methyl-benzimidazol-l-yl) methyl]biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Yield: 70.6 % of theoretical, Melting point: 219-221 °C C26H26N2O2 (398.51) Calculated: C 78.36 H 6.58 N 7.03 Found: 78.49 6.53 6.98 Example 86 ’ — [ (2-n-Butyl-5-methanesulphonamino-benzimidazol-l-yl) methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert. butyl 4 * - [ (2 -n-buty 1-5-methanesulphonaminobenzimidazol-l-yl) -methyl] biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Yield: 75.7 % of theoretical, Melting point: 242-244 °C C26H„N30aS (477.59) Calculated: C 65.39 H 5.70 N 8.80 S 6.71 Found: 65.52 5.65 8.55 6.51 Example 87 4·-[(7-n-Butanoyloxy-2-n-butyl-4-methyl-benzimidazol-lyl) -methyl]bipheny1-2-carboxylic acid Prepared in analogous manner to Example 60 from 4*-[(2161 n-butyl-7-hydroxy-4-methyl-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and butyric acid chloride in pyridine.
Yield: 29.1 % of theoretical, Melting point: 240-242 °C C30H32N2O4 (484.60) Calculated: C 74.63 H 6.66 N 5.78 Found: 74.20 6.76 5.87 Example 88 4'-[(2-n-Butyl-6-ethoxycarbonylamino-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 41-[(2-n-butyl-6-ethoxycarbonylaminobenzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Yield: 88.2 % of theoretical, Melting point: 240-242 °C C28H2eN3O3 (471.55) Calculated: C 71.32 H 6.20 N 8,91 Found: 71.06 6.36 9.04 Example 89 4'-[(2-n-Butyl-6-isopropylsuIphonamino-benzimidazol-lyl)-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-buty1-6-isopropylsulphonaminobenzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Yield: 91.5 % of theoretical, Melting point: 155-157 °C C28H31N3O4S (505.63) Calculated: C 66.51 H 6.18 N 8.31 S 6.34 162 Found: 66.26 6.33 8.34 6.43 Example 90 4'-[(2-n-Butyl-4-nitrobenzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4' (2-n-butyl-4-nitrobenzimidazol-l-yl)methyl]bipheny1-2-carboxylate and trifluoroacetic acid/methylene chloride.
Yield: 84.6 % of theoretical, Melting point: 238-240 °C C25H23N3O4 (429.48) Calculated: C 69.92 H 5.40 N 9.78 Found: 69.85 5.43 9.67 Example 91 4' — [ (2-n-Butyl-4-butanoylamino-benzimidazol-l-yl) methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-4-butanoylamino-benzimidazol1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Yield: 96.1 % of theoretical, Melting point: 270-271 °C C29H31N3O3 (469.58) Calculated: C 74.18 H 6.65 N 8.95 Found: 74.02 6.74 8.99 163 Example 92 4'-((2-n-Butyl-4-ethylaminocarbonylamino-benzimidazol-lyl)-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4' -[ (2-n-butyl-4-ethylamino-carbonylaminobenz imidazol-l-yl) -methyl] biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Yield: 87.5 % of theoretical, Melting point: 344-346 °C (decomposition) C28H30N,O3 (470.57) Calculated: C 71.47 H 6.43 N 11.91 Found: 71.51 6.29 11.48 Example 93 4' — [ (2- (3-Pyridyl j -benzimidazol-l-yl) -methyl]biphenyl-2carboxylie acid Prepared in analogous manner to Example 9 from tert.butyl 41-[(2-(3-pyridyl)-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Yield: 73.3 % of theoretical, Melting point: 249-251 °C C26H19N3O2 (405.46) Calculated: C 77.02 H 4.72 N 10.36 Found: 76.85 4.72 10.15 164 Example 94 4' — [(2-n-Butyl-5-methyl-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4*-[(2-n-butyl-5-methyl-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Yield: 58.8 % of theoretical, Melting point: 188-190 °C (decomposition) C26H26N2O2 (398.51) Calculated: C 78.36 H 6.58 N 7.03 Found: 78.21 6.62 6.98 Example 95 4’—[(2-n-Butyl-6-dimethylamino-benzimidazol-l-yl) methyl]biphenyl—2-carboxylic acid trifluoroacetate Prepared in analogous manner to Example 9 from tert.butyl 41-[(2-n-butyl-6-dimethylamino-benzimidazoll-yl )-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 65.4 % of theoretical, C27H29N3O2 X CF3COOH (541.58) Calculated: C 64.31 H 5.58 N 7.76 Found: 64.53 5.66 7.89 165 Example 96 41-[(2-n-Butyl-5-(tert.butoxycarbonylaminoacetamino)benzimidazol>l-yl)-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 72 from ethyl 4·-[(2-n-butyl-5-(tert.butoxycarbonylaminoacetamino)benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and 2N sodium hydroxide.
Yield: 16.7 % of theoretical, Melting point: 149-151 °C C32H36N4O5 (556.66) Calculated: C 69.05 H 6.52 N 10.06 Found: 69.12 6.32 9.87 Example 97 * — [(2-n-Butyl-5,6-dimethyl-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-5,6-dimethyl-benzimidazol-lyl)-methyl]biphenyl-2-carb0xylate and trifluoroacetic acid in methylene chloride.
Yield: 17.5 % of theoretical, Melting point: 222-225 °C C27H28N2O2 (412.50) Calculated: C 78.62 H 6.84 N 6.79 Found: 78.36 6.90 6.83 166 Example 98 41-[(2-(2,2-Dimethylpropyl)-5,6-dimethyl-benzimidazol-lyl )-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4*-((2-(2,2-dimethylpropyl)-5,6-dimethylbenzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride. Ίθ Yield: 45 % of theoretical.
Melting point: from 115 °C (amorphous) C28H30N2O2 (426.60) Calculated: C 78.83 H 7.09 N 6.57 Found: 78.64 7.11 6.89 Example 99 4·-[(2-Benzyl-5,6-dimethyl-benz imidazol-l-yl)-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4»-[(2-benzyl-5,6-dimethyl-benzimidazol-lyl) -methyl] biphenyl-2 -carboxylate and trifluoroacetic acid in methylene chloride. 2$ Yield: 68 % of theoretical, Melting point: 252-255 °C C3oH28N202 (446.60) Calculated: C 80.69 H 5.87 N 6.27 Found: 80.94 5.76 5.97 .30 Example 100 4·-[(2—(2-Methylbutyl)-5,6-dimethyl-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid 167 Prepared in analogous manner to Example 9 from tert.butyl 4’-[(2-(2-methylbutyl)-5,6-dimethylbenzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 57 % of theoretical, Melting point: 211-215 °C C28H30N2O2 (426.60) Calculated: C 78.84 H 7.09 N 6.57 Found: 78.67 7.24 6.43 Example 101 · — [2— (Cyclohexylmethyl-5,6-dimethyl-benzimidazol-l-yl) methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-[2-(cyclohexylmethyl-5,6-dimethylbenzimidazol-l-yl) -methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 31 % of theoretical, Melting point: 199-201 °C C30H32N2O2 (452.60) Calculated: C 79.61 Found: 79.45 H 7.13 7.17 N 6.19 6.06 Example 102 4'—[2—(Cyclohexylmethyl-5,6-dichloro-benzimidazol-l-yl)methyl]bipheny1-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-cyclohexylmethy1-5,6-dimethylbenzimidazol-l-yl) -methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 39 % of theoretical, Melting point: 219-222 °C C28H26C12N2O2 (493.40) 168 Calculated: C 68.16 H 5.31 N 5.68 Cl 14.37 Found: 67.97 5.29 5.52 14.12 Example 103 * -1(2-(2-Methylbutyl)-naphtho[2,3-d]imidazol-l-yl)methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 41-[(2-(2-methylbutyl)-naphtho[2,3-d]imidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 64 % of theoretical, Melting point: 206-208 °C C30H28N2O2 (448.60) Calculated: C 80.33 H 6.29 N 6.25 Found: 80.20 6.36 6.24 Example 104 ί ’ 4·-[(2-n-Propyl-naphtho(2,3-d]imidazol-l-yl)-methyl]biph enyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert·butyl 4' - [(2-n-propyl-naphtho[2,3-d]imidazol-l-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 85 % of theoretical, Melting point: 269-272 °C C28H2aN2O2 (420.50) Calculated: C 79.98 H 5.75 N 6.66 Found: 79.87 5.68 6.48 169 Example 105 4(2-n-Butyl-5,6-dichloro-benzimidazol-l-yl)-methyl]bipheny1-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4 *-[(2-n-butyl-5,6-dichloro-benzimidazol-lyl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 50 % of theoretical, Melting point: 237-239 °C C25H22Cl2N2O2 (453.40) Calculated: C 66.23 H 4.89 N 6.18 Cl 15.64 Found: 66.10 4.82 6.05 15.42 Example 106 *-[ (2-Cyclohexylmethyl-5,6-dimethoxy-benzimidazol-lyl) -methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-((2-cyclohexylmethy1-5,6-dimethoxybenzimid-azol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 45 % of theoretical, Melting point: 245-247 °C C30H32N2O4 (484.60) Calculated: C 74.36 H 6.66 N 5.78 Found: 74.11 6.58 6.02 Example 107 4·-[(2-n-Butyl-5,6-dimethoxy-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-5,6-dimethoxy-benzimidazol-1170 yl)-methyl]bipheny1-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 52 % of theoretical, Melting point: 257-259 °C C»W« (444.50) calculated: C 72.95 H 6.35 N 6.30 Found: 72.77 6.26 6.49 Example 108 4'-[(2-Cyclopentylmethyl-5,6-dimethoxy-benzimidazol-lyl) -methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert. butyl 4' -.((2-cyclopentylmethy 1-5,6-dimethoxybenz imidazol-l-yl) -methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 47 % of theoretical, Melting point: 233-234 eC C29H30N2O4 (470.60) Calculated: C 74.02 H 6.43 N 5.95 Found: 73.96 6.56 6.18 Example 109 4' - [ (2- (3-Methylbutyl) -5,6-dimethoxy-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert. butyl 4' - [ ( 2^- (3-methylbutyl) -5,6-dimethoxybenz imidazol-l-yl) -methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 39 % of theoretical, Melting point: 237-239 °C C28H3ON2Ot (458.60) Calculated C 73.34 H 6.59 M 6.11 171 Found: 73.50 6.48 6.02 Example 110 4'-[(2—Cyclohexy1-5,6-dimethyl-benzimidazol-l-yl)methyl)biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4’-[(2-cyclohexyl-5,6-dimethyl-benzimidazol10 1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 27 % of theoretical.
Melting point: 240-242 °C C29H30N2O2 (438.60) Calculated: C 79.42 H 6.89 N 6.39 Found: 79.30 7.02 6.39 Example 111 I 4’—[(2-(l-Butyn*4—yl)-benzimidazol—1-yl)— methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-(l-butyn-4-yl)-benzimidazol-l-yl)25 methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 55 % of theoretical.
Melting point: 218-221 °C C25H20N2O2 (380.50) Calculated: C 78.93 H 5.30 N 7.36 Found: 78.97 5.24 7.31 172 Example 112 4' — [ (2-Cyclopentyl-5,6-dimethyl-benzimidazol-l-yl) methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-cyclopentyl-5,6-dimethyl-benzimidazoll-yl)-methyl] biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 75 % of theoretical, Melting point: 262-265 °C C2eH2eN2O2 (424.50) Calculated: C 79.22 H 6.65 N 6.60 Found: 78.99 6.54 6.67 Example 113 4·—[(2-n-Butyl-5-and 6-fluoro-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4·-[(2-n-butyl-5-and 6-fluoro-benzimidazol-lyl)-methyl)biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 80 % of theoretical, Melting point: 167-169 °C C25H23FN2O2 (402.50) calculated: C 74.61 H 5.76 N 6.96 Found: 74.57 5.77 7.05 Example 114 4’-[(2-n-Butyl-5-and 6-benzoyl-benzimidazol-l-yl)methyl)biphenyl-2-carboxylic acid 173 Prepared in analogous manner to Example 9 from tert.butyl 4’-[(2-n-butyl-5-benzoyl-and 6-benzoylbenzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 58.5 % of theoretical, Melting point: 180-182 °C C32H23N2O3 (488.60) Calculated: C 78.67 H 5.78 N 5.73 Found: 78.75 5.74 5.63 Example 115 4' - [ (2-n-Butyl-5-and 6-trifluoromethyl-benzimidazol-l?yl)-methyl]biphenyl-2-carboxylie acid Prepared in analogous manner to Example 9 from tert1butyl 4 ’ - [(2-n-butyl-5-and 6-trifluoromethylbenzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 85 % of theoretical, Melting point: 172-174 °C C26H23F3N2O3 (452.50) Calculated: C 69.01 H 5.12 N 6.19 Found: 69.10 5.24 6.11 Example 116 4'(2-n-Butyl-4-cyano-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4·-[(2-n-butyl-4-cyano-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 72 % of theoretical, Melting point: 190-192 °C 174 C26H23N3O2 (4 09.49) Calculated: C 76.26 H 5.66 N 10.62 Found: 76.01 5.72 10.51 Example 117 ’ — [ (2-n-Buty1-5-and 6-n-butylaminocarbonylbenz imidazol-l-yl) -methyl ] biphenyl-2 -carboxyl ic acid Prepared in analogous manner to Example 9 from tert. butyl 4' - [ (2-n-butyl-5-and 6-n-butylamino-carbonylbenzimidazol-l-yl) -methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 69 % of theoretical, Melting point: from 88 °C (decomposition) C30H33N3O3 X 1/2 CF3COOH (483.60) Calculated: C 68.88 H 6.25 N 7.77 Found: . 68.65 6.32 7.71 Example 118 ’ - [ (2-n-Butyl-6-carboxy-benzimidazol-l-yl) -methyl] biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4’-[(2-n-butyl-6-carboxy-benzimidazol-l-yl) · methyl] biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 91 % of theoretical, Melting point: 315-320 °C (decomposition) C2BH24N2O<, (428.50) Calculated: C 72.88 H 5.65 N 6.54 Found: 72.74 5.66 6.55 175 Example 119 4'-[(2-n-Butyl-5-carboxy-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4·-[(2-n-butyl-5-carboxy-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 63 % of theoretical.
Melting point: 247-248 °C C26H2«N2O, (428.50) Calculated: C 72.88 H 5.65 N 6.54 Found: 72.76 5.52 6.52 Example 120 4(2-n-Butyl-6-aminocarbonyl-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4 * -((2-n-butyl-6-aminocarbonyl-benzimidazol1—yl)—methyl]biphenyl—2—carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 45 % of theoretical, Melting point: 243-244 °C C26H25N3O3 X 1/2 H2O (436.51) Calculated: C 71.54 H 6.00 N 9.63 Found: 71.34 6.16 9.45 Example 121 4·—((2-n-Butyl-5-aminocarbonyl-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid 176 Prepared in analogous manner to Example 9 from tert.butyl 4(2-n-butyl-5-aminocarbonyl-benziraidazol1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 55 % of theoretical, Melting point: 227-228 °C C26H25N3O3 x 1/2 H2O (436.51) Calculated: C 71.54 H 6.00 N 9.63 Found: 71.42 5.94 9.46 Example 122 4(2-n-Butyl-5-and 6-cyano-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4·-[(2-n-butyl-5-and 6-cyano-benzimidazol-lyl) -methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 70 % of theoretical, Melting point: 214-215 °C C26H23N3O2 (409.50) Calculated: C 76.26 H 5.66 N 10.26 Found: 76.06 5.44 10.11 Example 123 4'(2-n-Butyl-5-(lH-tetrazol-5-yl)-benzimidazol-l-yl) methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-5-(lH-tetrazol-5-yl)benzimidazol-l-yl)-methyl)biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 66 % of theoretical, 177 Melting point: 249-250 °C C26H24N6O2 (452.50) Calculated: C 69.01 Found: 68.92 H 5.35 5.48 N 18.57 18.78 Example 124 4*-((2-n-Butyl-5-and 6-(lH-tetrazol-5-yl)-benzimidazoll-yl) -methyl]biphenyl-2-carboxylic acid _- _ Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-buty1-5-and 6-(lH-tetrazol-5-yl)benz imidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 55 % of theoretical, Melting point: from 220 °C (decomposition) C26H2«N6O2 (452.50) Calculated: C 69.01 H 5.35 N 18.57 Found: 68.92 5.41 18.35 Example 125 Tert.butyl 4’-[(2-n-butyl-5-dimethylaminosulphonyl25 benzimidazol-l-yl)-methylJbiphenyl-2-carboxylate Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-5-dimethylaminosulphonyl-3-N30 oxido-benz imidazol-l-yl) -methyl )biphenyl-2-carboxylate by catalytic hydrogenation in the presence of Raney nickel and subsequent reaction with trifluoroacetic acid in methylene chloride.
Yield: 92 % of theoretical, Melting point: 240-242 °C C27H2eN3O,S (491.60) Calculated: C 65.97 H 5.95 N 8.55 S 6.52 178 Found: 65.41 6.09 8.46 6.60 Example 126 41 - [ (2-n-Butyl-5-and 6-methoxycarbonylbenzimidazol-l yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl 0.71 g (l.o mmol) of 4(2-n-buty1-5-and 6methoxycarbonyl-benz imidazol-l-yl) -methyl ] -2- (1triphenylmethyl-tetrazol-5-yl)-biphenyl are heated with 25 ml of 5 % strength methanolic ammonia at 125-130 °C for 16 hours in a pressure vessel. After cooling, the solvent is distilled off, the residue is taken up in dilute acetic acid and extracted three times using ethyl acetate. The combined ethyl acetate phases are washed using sodium chloride solution, dried over sodium sulphate, evaporated and the residue is purified over a silica gel column using methylene chloride/ethanol 25:1 as eluting agent.
Yield: 0.34 g (73 % of theoretical), Melting point: 136-138 °C C27H26N6O2 (466.56) Calculated: C 69,50 H 5.57 N 17,98 Found: 69.42 5.33 17.44 Example 127 ’ — [(2-n-Butyl-5-and 6-n-butylaminocarbonylbenz imidazol-l-yl) -methyl ] -2- (lH-tetrazol-5-yl) -biphenyl 216 mg (1.05 mmol) of dicyclohexylcarbodiimide and 141 mg (1.05 mmol) of 1-hydroxybenzotriazole hydrate are dissolved in 30 ml of acetonitrile and 452 mg (1.00 mmol) of 4’—((2—n—butyl—5—and 6-carboxy-benzimidazol-lyl)-methyl)-2-(lH-tetrazol-5-yl)-biphenyl are added. 179 After stirring for 30 minutes at ambient temperature, 146 mg (2.00 mmol) of n-butylamine are added and the reaction mixture is stirred for 4 hours at ambient temperature. The dicyclohexylurea obtained is filtered off and the filtrate is evaporated. The residue obtained is taken up in methylene chloride and washed once using 5 % strength sodium bicarbonate solution and once using sodium chloride solution. After evaporating once again, the final product is obtained by chromatography on a silica gel column (eluting agent: methylene chloride/ethanol = 25:1).
Yield: 95 mg (19 % of theoretical), Melting point: 245-247 °C C30H33N7O (507.63) Calculated: C 71.00 H 6.50 N 19.30 Found: 70.77 6.66 19.36 Example 128 4’-[(2-n-Butyl-5-and 6-aminocarbonyl-benzimidazol-l-yl)methyl)-2-(lH-tetrazol-5-yl)-biphenyl Prepared in analogous manner to Example 127 from 4’-[(2n-butyl-5-aiid 6-carboxy-benzimidazol-l-yl) -methyl)-2(lH-tetrazol-5-yl)-biphenyl.
Yield: 17 % of theoretical, Melting point: 225-227 °C C26H2SN7O (451.62) Calculated: C 69.98 H 5.54 N 21.62 Found: 69.85 5.30 21.48 Example 129 4'—[(2-n-Butyl-5-and 6-hydroxymethyl-benzimidazol-l-yl)methyl)-2-(lH-tetrazol-5-yl)-biphenyl 180 452 mg (1.00 mmol) of 4 ·-[(2-n-butyl-5-and 6-carboxybenzimidazol-l-yl) -methyl]-2-(lH-tetrazol-5-yl) -biphenyl are dissolved in 20 ml of tetrahydrofuran and 67.0 mg (1.75 mmol) of lithium aluminium hydride are added. The suspension is stirred at 40 °C for 4 hours and then separated using 20 ml of water/ethanol (1:1). After filtering over kieselguhr, the product is evaporated and chromatographed on silica gel (eluting agent: methylene « chloride/ethanol =9:1 with 1 % ammonia added).
Yield: 90 mg (21 % of theoretical), Melting point: 173-175 °C C26H26N6O (438.54) Calculated: C 71.50 H 5.96 N 19.20 Found: 71.32 6.06 19.02 The following compound is obtained in analogous manner: · — [ (2-n-buty 1-5-and 6- (n-butylaminomethyl) -benzimidazol-l-yl) -methyl]-2-(lH-tetrazol-5-yl)-biphenyl melting point: 146-149 °C Example 130 · — [(2-n-Butyl-5-and 6-carboxy-benzimidazol-l-yl)methyl]-2-(lH-tetrazol-5-yl)-biphenyl 2.1 g (3.0 mmol) of 4*-[(2-n-buty1-5-and 6methoxycarbonyl-benz imidazol-l-yl) -methyl] -2- (1triphenylmethyl-tetrazol-5-yl)-biphenyl are dissolved in 100 ml of ethanol while heating, treated at 40 °C with 25 ml of IN sodium hydroxide and stirred at ambient temperature for 60 hours. The reaction solution is evaporated, the residue obtained is dissolved in iced water and brought to pH 4-5 using 2N acetic acid. The crude product precipitated is filtered off under 181 suction, washed until it is neutral using water and purified over a silica gel column (eluting agent: methylene chloride/ethanol = 9:1 with 1 % of glacial acetic acid added).
Yield: 0.65 g (48 % of theoretical).
Melting point: 188-190 °C C26H2AN6O2 (452.60) Calculated: C 68.80 H 5.53 N 18.52 Found: 68.63 5.34 18.65 Example 131 · -[ (2-n-Butyl-7-cyano-benzimidazol-l-yl) -methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4·-[(2-n-butyl-7-cyano-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 68 % of theoretical, Melting point: 190-192 °C C26H23N3O2 (409.49) Calculated: C 76.26 H 5.66 N 10.26 Found: 75.99 5.46 10.25 Example 132 ’ — [ (2-n-Butyl-5,7-difluoro-benzimidazol-l-yl) 30 methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-5,7-difluoro-benzimidazol-1yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 49 % of theoretical. 182 Melting point: from 155 °C (amorphous) C25H22F2N2O2 (420.40) Calculated: C 71.41 H 5.27 N 6.66 Found: 71.38 5.09 6.39 Example 133 '-[ (2-n-Butyl-5-acetyl-benzimidazol-l-yl) -methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-5-acetyl-benz imidazol-l-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 59.5 % of theoretical.
Melting point: 182-184 °C C27H26N2O3 (426.50) Calculated: C 76.03 H 6.14 N 6.57 Found: χ 75.89 6.35 6.33 Example 134 4·-[(2-Cyclohexylmethyl-5,6-dihydroxy-benzimidazol-lyl)-methyl]biphenyl-2-carboxylic acid 0.29 ml (3 mmol) of boron tribromide is added dropwise to a suspension of 242 mg (0.5 mmol) of 4(2-cyclohexylmethyl-5,6-dimethoxy-benzimidazol-l-yl)-methyl]biphenyl -2 -carboxylic acid in 25 ml of dichloromethane at -5 °C. When the addition is complete, the cooling bath is removed and the mixture is stirred at ambient temperature for 5 hours. 20 ml of methanol are then added while the mixture is cooled with ice, then the reaction mixture is evaporated to dryness and the residue is suspended in 10 ml of water while stirring. 183 The crude product precipitated is filtered off under suction, washed with a further 10 ml of water, dried and chromatographed over a silica gel column (eluting agent: dichloromethane/ethanol = 9:1).
Yield: 51 mg (22 % of theoretical), Melting point: amorphous C2bH28N2Oa (456.50) Calculated: C 73.66 H 6.18 N 6.14 Found: 73.79 6.31 6.22 The following compounds are obtained in analogous manner: 4’—[(2-n-butyl-5-hydroxy-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid melting point: 306-307 °C 4(2-n-butyl-4-hydroxy-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid melting point: 292-293 °C 4’-[(2-n-butyl-7-hydroxy-benzimidazol-1-yl)-methyl]biphehyl-2-carboxylic acid melting point: 295-297 °C Example 135 ’ -[ (2-(3-Methylbutyl) -5-methoxy-6-hydroxy-benzimidaz0l1-yl)-methyl]biphenyl-2-carboxylic acid and 4 ’ - [ (2—(3-methylbutyl) -5-hydroxy-6-methoxy-benzimidazoll-yl)-methyl]biphenyl-2-carboxylic acid g of aluminium trichloride are added to a suspension of 600 mg (1.3 mmol) of 4’-[(2-(3-methylbutyl)-5,6dimethoxy-benz imidazol-l-yl) -methyl ] biphenyl-2 carboxylic acid in 50 ml of dry dichloromethane and the 184 mixture is heated under reflux for 15 minutes. The solvent is then distilled off, the residue is filtered off under suction, washed using 30 ml of water and dried. 360 mg (62 % of theoretical) of a mixture of the isomeric products is obtained after chromatographing over silica gel (eluting agent: dichloromethane/ethanol = 9:1).
To separate the isomers, 230 mg of the mixture are chromatographed again over silica gel (eluting agent: dichloromethane/ethanol = 11:1). 80 mg of 4*-((2-(3methylbutyl) -5-methoxy-6-hydroxy-benzimidazol-l-yl)methyl]bipheny 1-2-carboxylic acid (melting point: 189192 °C) C27H28N2O4 (444.50) Calculated: C 72.95 H 6.35 N 6.30 Found: 72.84 6.32 6.19 and 30 mg of 4'-[ (2-(3-methylbutyl)-5-hydroxy-6-methoxy benzimidazol-l-yl) -methyl]biphenyl-2-carboxylic acid (melting point: 188-190 °C) C27H28N2O4 (444.50) Calculated: C 72.95 H 6.35 N 6.30 Found: 73.13 6.39 6.41 are thus obtained.
Example 136 Ethyl 4 · — [ (2—n—b^ityl—7—n—propylamino—benzimidazol—l—yl) methyl]biphenyl-2-carboxylate 2.0 g (4.7 mmol) of ethyl 4·-((7-amino-2-n-butyl35 benzimidazol-l-yl) -methyl]biphenyl-2-carboxylate are dissolved in 50 ml of ethanol and 0.53 ml (7.5 mmol) of propionaldehyde and 0.5 g of 10 % palladium on carbon 185 are added and the mixture is hydrogenated for 2 hours at ambient temperature and 5 bar hydrogen pressure. The catalyst is then filtered off under suction and the solvent is removed in vacuum. The oily residue is purified over an aluminium oxide column (neutral, activity II-III), the column being eluted with cyclohexane/methylene chloride = 3:1 and 1:1. The appropriate fractions are combined and rotary evaporated.
Yield: 2.0 g (90.9 % of theoretical), oil, Rf value: 0.50 (Silica gel: methylene chioride/ethanol) = 19:1) The following compounds are obtained in analogous manner: tert.butyl 4'-[(2-n-butyl-5-n-pentylamino-benzimid-azol1-yl)-methyl]biphenyl-2-carboxylate Rf value: 0.45 (Aluminium oxide, methylene chloride) tert. butyl 4 ' - [ (2-n-butyl-6-n-pentylamino-benzimid-azol1-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.40 (Silica gel: methylethylketone/xylene = 1:1) tert. butyl 4' - [ (2-n-butyl-6-n-butylamino-benzimidazol-lyl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.50 (Silica gel: methylethylketone/xylene = 1:1) tert.butyl 4’-[(2-n-butyl-6-(2-cyclohexyl-ethylamino)benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.40 (Silica gel: ethyl acetate/petroleum ether = 60:40) tert.butyl 4 * -[(2-n-buty1-6-(cis-and trans-decahydronaphth-2-yl-amino)-benzimidazol-l-yl)-methyl]biphenyl-2186 carboxylate oil, Rf value: 0.65 (Aluminium oxide plate: petroleum ether/ethyl acetate = 9:1) Example 137 4·-[(2-n-Butyl-7-n-propylamino-benzimidazol-l-yl)methyl]bipheny1-2-carboxylic acid Prepared in analogous manner to Example 72 from ethyl 4(2-n-butyl-7-n-propylamino-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate and 2N sodium hydroxide/ethanol.
Yield: 85.7 % of theoretical, Melting point: 262-263 °C C28H31N3O2 (441.57) Calculated: C 76.16 H 7.08 N 9.52 Found: 76.35 7.26 9.60 Example 138 4’-[(2-n-Butyl-5-and 6-nitro-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4*-[(2-n-butyl-5-and 6-nitro-benzimidazol-lyl) -methyl ]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 54.4 % of theoretical, Melting point: 223-224 °C C25H23N3O4 (429.48) Calculated: C 69.92 H 5.60 N 9.78 Found: 69.81 5.47 9.72 187 Example 139 4'(2-n-Butyl-7-n-butylsulphonamino-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 72 from ethyl 4' -((2-n-butyl-7-n-butylsulphonamino-benzimidazol-l-yl)methyl]bipheny1-2-carboxylate and sodium hydroxide in ethanol.
Yield: 94.7 % of theoretical.
Melting point: 225-226 °C C29H33N3O,S (519.66) Calculated: C 67.03 H 6.40 N 8.09 S 6.17 Found: 66.92 6.63 8.09 5.91 Example 140 4·—[(2-n-Butyl-5-n-pentylamino-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid hemi-trifluoroacetate Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-5-n-pentylamino-benzimidazol1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 92.3 % of theoretical, Melting point: 155-157 °C C30H35N3O4 X 1/2 CF3COOH (526.64) Calculated: C 70.70 H 6.79 N 7.98 Found: 70.84 6.94 8.05 188 Example 141 4(2-n-Butyl-6-cyclohexylaminocarbonylaminobenzimidazol-l-yl)-methyl)-2-amino-biphenyl g (3.2 mmol) of 4'-[(2-n-butyl-6-cyclohexylaminocarbonylamino-benzimidazol-l-yl) -methyl ] -2-phthal iminobiphenyl are dissolved in 20 ml of methanol and 10 ml of dimethylformamide and, after adding 20 ml of 40 % strength methylamine solution, are stirred for 2 hours at ambient temperature. The mixture is evaporated to dryness in vacuum. The remaining residue is suspended in ether and the insoluble N-methyl-phthalimide is filtered off. The filtrate is evaporated to dryness in vacuum and purified over silica gel (grain size: 0.063-0.2 mm, eluting agent: methylene chloride with 0.5-2 % ethanol). The resulting product is suspended in ether, filtered under suction, washed using ether and dried in vacuum. Yield: 1.37 g (85.6 % of theoretical), Melting point: 209-211 °C C31H37N5O (495.68) Calculated: C 75.12 H 7.52 N 14.13 Found: 75.33 7.57 14.01 The following compound is obtained in analogous manner: 4·-[(2-n-butyl-7-hydroxy-4-methyl-benzimidazol-l-yl)methyl]-2-amino-biphenyl melting point: 249-250 °C 189 Example 142 4·-[(2-n-Butyl-7-hydroxy-4-methyl-benzimidazol-l-yl)methyl]-2-aminomethyl-biphenyl 3.3 g (7.1 mmol) of 4(7-benzyloxy-2-n-butyl-4-methylbenzimidazol-l-yl)-methyl]-2-cyano-biphenyl are dissolved in 100 ml of methanol and hydrogenated at ambient temperature in the presence of 0.5 g of palladium (10 % on carbon) at 5 bar of hydrogen. After hours the catalyst is filtered off. 20 ml of 20 % strength ammonia in methanol is added to the filtrate and the mixture is hydrogenated again at 70 °C in the presence of 0.5 g of Raney nickel at 5 bar of hydrogen. After 4 hours the catalyst is filtered off under suction and the filtrate is evaporated to dryness in vacuum. The crude crystalline product is suspended in ether, filtered under suction, washed using ether and dried in vacuum.
Yield: 2.6 g (92.8 % of theoretical), Melting point: 207-212 °C C26H28N3O (399.53) Calculated: C 78.16 H 7.32 N 10.52 Found: 77.97 7.34 10.51 Example 143 ’ —[(2-n-Butyl-6-cyclohexylaminocarbonylaminobenzimidazol-l-yl)-methyl]-2-trifluoroacetamino-biphenyl 0.35 g (0.7 mmol) of 4·-[(2-n-buty1-6-cyclohexylaminocarbony lamino-benz imidazol-l-yl)-methyl]-2-aminobiphenyl, dissolved in 15 ml of methylene chloride and 0.85 ml (6.1 mmol) of triethylamine, is cooled to -60 °C 190 and 0.85 ml of trifluoroacetic anhydride in 2 ml of methylene chloride is added dropwise while stirring. The mixture is allowed to rise to ambient temperature overnight and is evaporated to dryness. The residue is purified over silica gel (eluting agent: methylene chloride with 0.5-2 % ethanol). The eluates collected are evaporated, crystallised from ether/benzene 60-80 °C and dried in vacuum.
Yield: 0.21 g (50 % of theoretical).
Melting point: 231-233 °C CssHaeFaNsOa (591.68) Calculated: C 66.99 H 6.13 N 11.83 Found: 66.83 5.96 11.71 The following compounds are obtained in analogous manner: · — [(7-benzyloxy-2-n-butyl-4-methyl-benzimidazol-l-yl)methyl]-2-trifluoroacetaminO-bipheny1 melting point: 147-149 °C 4’ —[ (2-n-butyl-7-hydroxy-4-methyl-benzimidazol-l-yl) methyl]-2-trifluoroacetaminomethyl-biphenyl melting point: 247-249 °C 4(7-benzyloxy-2-n-butyl-4-methyl-benzimidazol-l-yl)methyl]-2-trif luoromethanesulphonamino-biphenyl oil, Rf value: 0.65 (Silica gel: petroleum ether/ethyl acetate = 1:1) 4'-[(2-n-butyl-7-trifluoromethanesulphonyloxy-4-methy1benzimidazol-l-yl)-methyl]-2trifluoromethanesulphonaminomethyl-biphenyl melting point: 137-139 °C 191 Example 144 *-[(2-n-Butyl-4-methoxy-benzimidazol-l-yl) methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4' - [ (2-n-butyl-4-methoxy-benzimidazol-l-yl)10 methyl]biphenyl-2-carboxylate and trifluoroacetic acid. Yield: 76.5 % of theoretical, Melting point: 179-181 °C C26H26N2O3 (414.51) Calculated: C 75.34 H 6.32 N 6.76 Found: 75.07 6.35 6.71 Example 145 4' -[ (2-n-Butyl-7-methoxy-benzimidazol-l-yl) -methyl]?0 biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4' - [(2-n-butyl-7-methoxy-benz imidazol-l-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid. Yield: 80 % of theoretical, Melting point: 260-261 °C C26H26N2O3 (414.51) Calculated: C 75.34 H 6.32 N 6.76 Found: 75.09 6.37 6.79 Example 146 · — [(5-Aminoacetamino-2-n-butyl-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid 192 Prepared in analogous manner to Example 9 from tert.butyl 4' — [(5-aminoacetamino-2-n-butyl-benzimidazoll-yl )-methyl]bipheny1-2-carboxylate and trifluoroacetic acid.
Yield: 40 % of theoretical, Melting point: 230-232 °C (decomposition) C27H28N4O3 (456.54) Calculated: C 71.03 H 6.18 N 12.27 Found: 70.83 6.36 11.98 Example 147 4' - ((2-n-Butyl-5-n-pentylamino-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid hemi-trifluoroacetate Prepared in analogous manner to Example 9 from tert.butyl 4'-((2-n-butyl-5-n-pentylamino-benzimidazol1-yl)-methyl)biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 92.3 % of theoretical, Melting point: 155-157 °C (decomposition) C30H35N3O2 X 1/2 CF3COOH (526.64) Calculated: C 70.70 H 6,79 N 7.98 Found: 71.04 7.14 8.05 Example 148 ’ — [(2-n-Butyl-6-methylamino-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid hemi-trifluoroacetate Prepared in analogous manner to Example 9 from tert.butyl 4'-[ (2-n-butyl-6-methylamino-benzimidazol-lyl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 77.3 % of theoretical, Melting point: 197-199 °C 193 C26H27N3O2 X 1/2 CF3COOH (470.53) Calculated: C 68.92 H 5.89 N 8.93 Found: 68.82 5.80 8.62 Example 149 41 -[ (2-n-Butyl-6-(N-butanoyl-methylamino) -benzimidazoll-yl )-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4’-[(2-n-butyl-6-(N-butanoyl-methylamino)benzimidazol-l-yl) -methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 70.3 % of theoretical.
Melting point: 165-167 °C C30H33N3O3 (483.62) Calculated: C 74.51 H 6.87 N 8.68 Found: 74.51 6.89 8.56 Example 150 4'-[(6-Aminocarbonylamino-2-n-butyl-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid trifluoroacetate Prepared in analogous manner to Example 9 from tert.butyl 4'-((6-aminocarbonylaminb-2-n-butyl-benz imidazol-l-yl )-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 93.8 % of theoretical, Melting point: 134-136 °C (amorphous) C26H26NaO3 X CF3COOH (556.54) Calculated: C 60.43 H 4.89 N 10.07 Found: 60.22 4.87 9.80 194 Example 151 ‘ - [ (2-n-Butyl-6-(n-hexylaminocarbonylamino)-benzimidazo 1-1-yl)-methyl]biphenyl-2-carboxylic acid trifluoroacetate Prepared in analogous manner to Example 9 from tert.butyl 4'(2-n-butyl-6-(n-hexylaminocarbonylamino)benz imidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 93.3 % of theoretical, Melting point: 138-140 °C C32H38NaO3 x CF3COOH (640.70) Calculated: C 63.74 H 6.14 N 8.74 Found: 63.66 6.19 8.51 Example 152 4’-[(2-n-Butyl-4-hydroxy-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-4-hydrbxy-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid. Yield: 72.5 % of theoretical, Melting point: 292-293 °C C25H24N2O3 (400.48) Calculated: C 74.98 H 6.04 N 7.00 Found: 74.85 6.13 6.91 195 Example 153 4'-[(2-n-Butyl-5-cyclohexylaminocarbonylaminobenzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid trifluoroacetate Prepared in analogous manner to Example 9 from tert.butyl 4’-[(2-n-buty1-5-cyclohexylaminocarbonylamino-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 81.1 % of theoretical.
Melting point: 176-177 °C (amorphous.) C32H36NaO3 x CF3COOH (638.69) Calculated: C 63.94 H 5.84 N 8.77 Found: 64.04 6.00 9.05 Example 154 * — [(2-n-Butyl-7-isopropylaminomethyl-benzimidazol-lyl)-methyl]biphenyl-2-carboxylic acid hydrate Prepared in analogous manner to Example 9 from tert.butyl 4’-[(2-n-butyl-7-isopropylaminomethylbenzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 53 % of theoretical, Melting point: 156-158 °C CZ9H33N3O2 x H2O (473.61) Calculated: C 73.54 H 7.45 N 8.87 Found: 73.69 7.37 8.91 196 Example 155 *-[(6-Aminothiocarbonylamino-2-n-buty1-benzimidazol-l yl)-methyl]biphenyl-2-carboxylic acid hemi-hydrate Prepared in analogous manner to Example 9 from tert.butyl 4·-[(6-aminothiocarbonylamino-2-n-butylbenzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 80.4 % of theoretical, Melting point: 147-149 °C C26H26N4O2S x 1/2 H2O (467.58) Calculated: C 66.80 H 5.81 N 6.85 Found: 66.92 5.91 6.66 Example 156 4(2-n-Butyl-6-cyclohexylaminothiocarbonylaminobenzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-((2-n-butyl-6-cyclohexylaminothiocarbony1amino-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 88.2 % of theoretical, Melting point: 223-225 °C (decomposition) C32H36N4O2S (540.72) Calculated: C 71.08 H 6.71 N 10.36 S 5.93 Found: 70.95 6.77 10.53 6.23 197 Example 157 · — [(2-n-Butyl-6-hydroxy-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-hydroxy-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid. Yield: 76.5 % of theoretical, Melting point: 264-266 °C C25H24N2O3 (400.48) Calculated: C 74.98 H 6.04 N 7.00 Found: 75.06 5.95 6.98 Example 158 ' -[(2-n-Butyl-7-(2-methoxy-ethoxy) -4-methy1benzimidazol-l-ylj -methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4 · - [(2-n-butyl-7-(2-methoxy-ethoxy)-4-methylbenzimidazol-l-yl) -methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 63.6 % of theoretical, Melting point: 205-207 °C C2aH32NzO4 (472.58) Calculated: C 73.71 H 6.82 N 5.93 Found: 73.48 6.64 6.15 Example 159 41 —[(2-n-Butyl-6-trifluoroacetylamino-benzimidazol-lyl)-methyl]biphenyl-2-carboxylic acid 198 Prepared in analogous manner to Example 9 from tert.butyl 4·-[(2-n-butyl-6-trifluoroacetylaminobenzimidazol-l-yl) -methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 69.6 % of theoretical, Melting point: 84-86 °C C27H2AN3O3F3 (495.50) Calculated: C 65.45 H 4.88 N 8.48 Found: 65.20 5.06 8.64 Example 160 4‘-((2-n-Butyl-4-cyclohexylaminocarbonylaminobenzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4·-[(2-n-butyl-4-cyclohexylaminocarbohylamino-benz imidazol-l-yl) -methyl) biphenyl-2 -carboxylate and trifluoroacetic acid.
Yield: 94.4 % of theoretical, Melting point: 242-244 °C (decomposition) C32H36N4O3 (524.66) Calculated: C 73.26 H 6.92 N 10.68 Found: 72.42 6.93 10.77 Example 161 ’ — [(6-Allylaminocarbonylamino-2-n-butyl-benzimidazol-l yl)-methyl]biphenyl-2-carboxylic acid trifluoroacetate Prepared in analogous manner to Example 9 from tert.butyl 4'-[(6-allylaminocarbonylamino-2-n-butylbenzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 96 % of theoretical, 199 Melting point: 90-92 °C C29H30N4O3 X CF3COOH (596.61) Calculated: C 62.41 H 5.24 N 9.39 Found: 62.20 5.17 9.13 Example 162 ’ -[ (6-Benzylaminocarbonylamino-2-n-butyl-benzimidazoll-yl) -methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4·-[(6-benzylaminocarbonylamino-2-n-butylbenzimidazol-l-yl) -methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 79.4 % of theoretical, Melting point: 244-245 °C C33H32N4O3 (532.64) Calculated: C 74.41 H 6.06 N 10.52 Found: 74.32 6.09 10.31 Example 163 (2-n-Butyl-6-(N-methylaminocarbonyl-n-pentylamino) benzimidazol-l-yl) -methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert. butyl 4 ’ - [ (2-n-buty1-6- (N-methylaminocarbonyl-npenty lamino) -benzimidazol-l-yl) -methyl ] biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 54 % of theoretical, Melting point: 149-152 °C C32H3eN4O3 (526.68) Calculated: C 72.98 H 7.27 N 10.64 Found: 72.95 7.27 10.73 Example 164 200 '-[ (5-Aminothiocarbonylamino-2-n-butyl-benzimidazol-iyl)-methyl]biphenyl-2-carboxylic acid hydrochloride Prepared in analogous manner to Example 9 from tert. butyl 41 -[ (5-aminothiocarbonylamino-2-n-butylbenzimidazol-l-yl) -methyl ] biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 66.6 % of theoretical, Melting point: 150-152 °C C26H27N4O2SC1 (495.04) Calculated: C 63.08 H 5.49 N 11.31 S 6.46 Found: 62.83 5.76 11.15 6.22 Example 165 4'(2-n-Butyl-5-formylamino-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 41 -[ (2-n-butyl-5-f ormylamino-benzimidazol-1yl)-methyl) biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 64.6 % of theoretical, Melting point: 229-230 °C C26H25N3O3 (427.51) Calculated: C 73.05 H 5.89 N 9.83 Found: 73.31 6.11 9.58 Example 166 · — [ (2-n-Butyl-5- (N-propanoyl-methy lamino) -benzimidazoll-yl) -methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4 ·-[ (2-n-butyl-5- (N-propanoyl-methylamino) benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and 201 trifluoroacetic acid.
Yield: 77.8 % of theoretical, Melting point: 178-180 °C C2gH31N3O3 (469.59) Calculated: C 74.18 H Found: 73.93 6.65 6.70 N 8.95 9.07 Example 167 4'-((2-n-Butyl-6-(N-methylaminocarbonyl-methylamino) benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from 15 tert.butyl 41-[(2-n-butyl-6-(N-methylaminocarbony1methylamino)-benzimidazol-l-yl)-methyl]biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 85.7 % of theoretical, Melting point: 163-165 °C 20 C28H30N4O3 (470.58) Calculated: C 71.46 H 6.42 N 11.91 Found: 71.33 6.64 11.74 Example 168 ’ — [ (2-n-Butyl-6- (N- (n-butylaminocarbonyl) -methylamino) benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4 ’ (2-n-butyl-6-(N-(n-butylaminocarbonyl)methylamino)-benzimidazol-l-yl)-methyl]biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 90 % of theoretical, Melting point: 145-147 °C C31H36N4O3 (512.65) Calculated: C 72.64 H 7.08 N 10.93 202 Found: 72.90 7.16 10.69 Example 169 4' - [ (2-n-Butyl-5- (N-methylaminocarbony 1-n-penty lamino) benzimidazol-l-yl) -methyl ]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from 1 o tert. butyl 4 ’ - [ (2-n-butyl-5- (N-methylaminocarbonyl-npentylamino) -benzimidazol-l-yl) -methyl ] biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 75 % of theoretical, Melting point: 240-242 °C 15 C32H38N3 (526.69) Calculated: C 72.97 H 7.27 N 10.64 Found: 72.78 7.23 10.66 Example 170 ·-[ (2-n-Butyl-6-(N-propanoyl-methylamino) -benzimidazoll-yl)-methyl)biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4' -[ (2-n-butyl-6-(N-propanoyl-methylamino) benzimidazol-l-yl) -methyl ]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 53.7 % of theoretical, Melting point: 152-154 °C C29H31N3O3 (469.59) Calculated: C 74.16 H 6.65 N 8.95 Found: 73.96 6.53 8.97 Example 171 4(6-Acetamino-2-n-butyl-benzimidazol-l-yl) -methyl]203 biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-[(6-acetamino-2-n-butyl-benziraidazol-l5 yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 87 % of theoretical, Melting point: 252-254 °C C27H27N3O3 (441.53) Calculated: C 73.45 H 6.16 N 9.52 Found: 73.28 5.95 9.39 Example 172 41-[(2-n-Butyl-6-propionylamino-benzimidazol-l-yl)methyl)biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from 20 tert.butyl 4'-[(2-n-butyl-6-propionylamino-benzimidazol1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 90 % of theoretical, Melting point: 269-271 °C C28H29N3O3 (455.56) Calculated: C 73.82 H 6.42 N 9.22 Found: 73.99 6.42 9.18 Example 173 30 4'-[(6-n-Butanoylamino-2-n-butyl-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4’-[(6-n-butanoyl-amino-2-n-butyl-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and 204 trifluoroacetic acid.
Yield: 79.1 % of theoretical, Melting point: 253-255 °C C29H31N3O3 (469.58) calculated: C 74.18 H 6.66 N 8.96 Found: 73.99 6.65 8.87 Example 174 4' — [ (2-n-Butyl-6-(n-butylaminocarbonylamino) -benzimidazo 1-1-yl)-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4 ' -[(2-n-butyl-6-(n-butylaminocarbonylamino)benzimidazol-l-yl) -methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 69.2 % of theoretical.
Melting point: 239-242 °C C30H34N4O3 (498.62) Calculated: C 72.27 H 6.87 N 11.24 Found: 71.92 6.86 10.93 Example 175 41 — [ (2—n—Butyl—6—(N—cyclohexylaminocarbonyl— methylamino) -benzimidazol-l-yl) -methyl ]bipheiiyl-2carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4 · -[(2-n-butyl-6-(N-cyclohexylaminocarbonylmethylamino)-benzimidazol-l-yl)-methyl]biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 80 % of theoretical, Melting point: 215-217 °C C33H38N4O3 (538.69) Calculated: C 73.58 H 7.11 N 10.40 205 Found: 73.52 7.19 .54 Example 176 · — [(2-n-Butyl-6-(N-(dimethylaminocarbonyl)methylamino)-benzimidazol-l-yl)-methyl]biphenyl-2carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4*-[(2-n-butyl-6-(N-(dimethylaminocarbonyl) methylamino)-benzimidazol-l-yl)-methylJbipheny1-2carboxylate and trifluoroacetic acid.
Yield: 66 % of theoretical, Melting point: 224-226 °C C29H32N4O3 (484.60) Calculated: C 71.88 H 6.66 N 11.56 Found: 71.61 6.92 11.27 Example 177 4·-[(2-n-Butyl-6-n-pentanoylamino-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4’-[(2-n-butyl-6-n-pentanoylaminobenzimidazol-l-yl) -methyl ]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 74.5 % of theoretical, Melting point: 253-255 °C C30H33N3O3 (483.61) Calculated: C 74.57 H 6.88 N 8.70 Found: 74.23 7.08 8.63 Example 178 206 4'-[(2-n-Butyl-6-(N-(dimethylaminocarbonyl)-amino)-benzi midazol-l-yl)-methyl]biphenyl-2-carboxylic acid tri fluoroacetate Prepared in analogous manner to Example 9 from tert.butyl 4' -((2-n-butyl-6-(N-(dimethylaminocarbonyl)amino)-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 83.1 % of theoretical, Melting point: 198-200 °C WW» X CF3COOH (584.60) Calculated: C 61.63 H 5.34 N 9.58 Found: 61.62 5.50 9.68 Example 179 4'-[(2-n-Butyl-6-(N-(n-butylaminocarbonyl)-methylamino)benzimidazol-l-yl)-methyl)biphenyl-2-carboxylicacid trifluoroacetate Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-(n-butylaminocarbonyl)methylamino)-benzimidazol-l-yl)-methyl]biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 70 % of theoretical.
Melting point: 152-154 °C C31H3eN4O3 x CF3COOH (626.68) Calculated: C 63.25 H 5.95 N 8.94 Found: 63.18 6.07 9.03 Example 180 4·-[(2-n-Butyl-6-(N-cyclohexylaminocarbonyl-n-pentylamino)-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid 207 Prepared in analogous manner to Example 9 from tert.butyl 4·-[(2-n-butyl-6-(N-cyclohexylaminocarbonyl n-pentylamino)-benzimidazol-l-yl)-methyl]biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 46.7 % of theoretical, Melting point: 134-137 °C C37H46N4O3 (594.80) Calculated: C 74.72 H 7.79 N 9.42 Found: 74.52 7.85 9.34 Example 181 Tert.butyl 4·-[(2-n-butyl-6-(N-acetyl-methylamino)benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate 4.5 g (9 mmol) of tert.butyl 4’(2-n-butyl-6acetylamino-benzimidazol-l-yl)-methyl]biphenyl-2carboxylate are dissolved in 50 ml of dimethyl formamide and 0.48 g (9 mmol + io %) of sodium hydride suspension in oil (50 % strength) is added. The reaction mixture is stirred for 30 minutes at 80 °C, cooled to ambient temperatue and treated with 1.5 g of methyl iodide (9 . mmol + 20 %) . When the reaction is completed, the mixture is evaporated in vacuum, taken up in ethyl acetate and washed using water. The organic phase is dried over sodium sulphate and evaporated in vacuum, a oily residue being Obtained. A yellowish oil is obtained after purifying over a silica gel column (grain size: 0.02-0.5 mm, eluting agent: methylene chloride/ethanol = 49:1, 24:1) .
Yield: 3.7 g (80.4 % of theoretical), oil, Re value: 0.75 (Silica gel: methylene chloride/ethanol = 19:1) C32H37N3O3 ( 511 · 66 ) Calculated: C 75.12 H 7.29 N 8.21 208 Found: 74.99 7.32 8.22 The following compounds are prepared in analogous manner: tert.butyl 4'-[(2-n-butyl-5-(N-propionyl-methylamino)benz imidazol-l-yl)-methyl] biphenyl-2-carboxylate oil, Rf value: 0.80 (Silica gel: ethyl acetate/ethanol/ammonia = 90:10:1) tert.butyl 4 ’ - [ (2-n-butyl-6-(N-propionyl-methylamino)benzimidazol-l-yl) -methyl ] biphenyl-2-carboxylate oil, R£ value: 0.65 (Silica gel: methylene chloride/ethanol = 19:1) Example 182 4' - [ (2-n-Butyl-6- (tetrahydropyran-2-yl-aminocarbonylamino) -benzimidazol-l-yl) -methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 7 from 4’-((6amino-2-n-butyl-benz imidazol-l-yl) -methyl]biphenyl-2carboxylic acid and tetrahydropyran-2-yl-isocyanate. Yield: 35.7 % of theoretical, Melting point: 172-174 °C C31H„N4O4 ( 562.64) Calculated: C 70.70 H 6.51 N 10.64 Found: 70.59 6.77 10.88 Example 183 ’ — [(2-n-Butyl-6-phenylacetamino-benzimidazol-i-yl) methyl] biphenyl-2-carboxylic acid hemi-tri fluoroacetate Prepared in analogous manner to Example 9 from 209 tert.butyl 4’—[(2-n-butyl-6-phenylacetaminobenzimidazol-l-yl) -methyl]biphenyl-2-carboxylate and trifluoroacetic acid. Yield: 29.2 % of theoretical, Melting point: 273-275 °C (decomposition) C33H31N3O3 x 0.5 CF3COOH (574.64) Calculated: C 71.07 H 5.53 N 7.31 Found: 71.01 5.60 7.11 Example 184 * — [ (2-n-Butyl-6- (N- (n-hexylaminocarbonyl) -cyclohexylami no) -benzimidazol-l-yl) -methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4’-[(2-n-butyl-6-(N-(n-hexylaminocarbonyl)cyclohexylamino) -benzimidazol-l-yl) -methyl]biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 97.1 % of theoretical.
Melting point: 196-197 °C C38HA8N«O3 (608.82) Calculated: C 74.97 H 7.95 N 9.20 Found: 74.75 7.92 9.19 Example 185 (2-n-Butyl-6-cyclohexylcarbonylamino-benzimidazol-lyl)-methyl]bipheny1-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4 · - [(2-n-butyl-6-cyclohexylcarbonylaminobenzimidazol-l-yl) -methyl ] biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 68.4 % of theoretical, Melting point: 298-300 °C (decomposition) 210 C32H35N3O4 (509.65) Calculated: C 75.41 H 6.92 N 8.24 Found: 75.38 6.78 8.11 Example 186 4' -[ (6-Benzyloxycarbonylamino-2-n-butyl-benzimidazol-lyl )-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-[(6-benzyloxycarbonylamino-2-n-butylbenzimidazol-l-yl) -methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 64.9 % of theoretical.
Melting point: 238-240 °C (decomposition) C33H31N3O4 (533.63) Calculated: C 74.28 H 5.86 N 7.87 Found: 74.14 5.97 7.72 Example 187 4’.-C(2-n-Butyl-6-(2-cyclohexyl-ethylamino)-benzimidazol-lr-yl) -methyl ]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(2-cyclohexyl-ethylamino)benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 66.6 % of theoretical, Melting point: 217-219 °C C33H3eN3O2 (509.69) Calculated: C 77.77 H 7.71 N 8.24 Found: 77.57 7.56 8.23 Example 188 211 * — [(2-n-Butyl-6-cyclohexylmethylaminocarbonylbenzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4·-[(2-n-butyl-6-cyclohexylmethylaminocarbonyl-benzimidazol-l-yl)-methyl]biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 80.4 % of theoretical.
Melting point: 239-241 °C C33H37N3O3 (523.67) Calculated: C 75.69 H 7.12 N 8.02 Found: 75.53 6.94 7.97 Example 189 '-[ (2-n-Butyl-6-cyclohexylaminocarbonyl-benzimidazol-lyl)-methyl ]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4 * -[(2-n-butyl-6-cyclohexylamino-carbonylbenz imidazol-l-yl)-methyl ]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 89.2 % of theoretical, Melting point: 305-308 °C (decomposition) C32H35N3O3 (509.65) Calculated: C 75.42 H 6.92 N 8.24 Found: 75.31 7.03 8.11 212 Example 190 · —((2-n-Butyl-6-(N-methyl-n-butylaminocarbonyl) benz imidazol-l-yl) -methyl) biphenyl-2 -carboxyl ic acid Prepared in analogous manner to Example 9 from tert. butyl 4 ’ - ((2-n-butyl-6- (N-methyl-n-butylaminocarbonyl) -benzimidazol-l-yl) -methyl]biphenyl-2-carboxyϊθ late and trifluoroacetic acid.
Yield: 94.5 % of theoretical, Melting point: 176-178 °C C31H35N3O3 (497.64) Calculated: C 74.82 H 7.09 N 8.44 15 Found: 74.98 7.21 8.50 Example 191 · - [ (2-n-Butyl-6-ethoxycarbonyl-benzimidazol-l-yl) 20 methyl)biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-((2-n-butyl-6-ethoxycarbonyl-benzimidazol25 1-yl) -methyl Jbiphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 59.7 % of theoretical, Melting point: 219-220 °C C28HZ8N2O4 (456.54) 30 Calculated: C 73.66 H 6.18 N 6.14 Found: 73.49 6.13 5.94 Example 192 15 4' - [ (2-n-Butyl-5-n-butylaminocarbonyl-benzimidazol-lyl) -methyl]biphenyl-2-carboxylic acid 213 Prepared in analogous manner to Example 9 from tert.butyl 4' - [(2-n-butyl-5-n-butylaminocarbony1benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 48.9 % of theoretical.
Melting point: 209-210 °C C30H33N3O3 (483.61) Calculated: C 74.51 H 6.88 N 8.69 Found: 74.54 6.79 8.79 Example 193 4·-[(2-n-Butyl-6-(3-cyclohexyl-piperidino)-benzimid15 azol-l-yl)-methyl]biphenyl-2-carboxylic acid sesquitrifluoroacetate Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(3-cyclohexyl-piperidino)benzimidazol-l-yl) -methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 85.0 % of theoretical.
Melting point: 155-157 °C C36H„N3O2 x 1.5 CF3COOH (720.80) Calculated: C 64.99 H 6.22 N 5.83 Found: 64.88 6.41 5.95 Example 194 · — [(2-n-Butyl-6-(cis-and trans-decahydronaphth-2ylamino)-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid dihydrochloride Prepared in analogous manner to Example 9 from tert.butyl 4'-((2-n-butyl-6-(cis-and trans214 decahydronaphth-2-ylamino)-benzimidazol-l-yl)methyl)biphenyl-2-carboxylate and trifluoroacetic acid. Yield: 24.0 % of theoretical, Melting point: from 132 °C C35H41N3O2 x 2 HC1 (608.65) Calculated: C 69.07 H 7.12 N 6.90 Found: 68.98 7.23 6.97 Example 195 (2-n-Butyl-6-cyclohexylamino-benzimidazol-l-yl) methyl)biphenyl-2-carboxylic acid sesquitrifluoroacetate Prepared in analogous manner to Example 9 from tert.butyl 4·-[(2-n-butyl-6-cyclohexylamino-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 99.0 % of theoretical, Melting point: 64-66 °C (amorphous) C31H3SN3O2 X 1.5 CF3COOH (652.68) Calculated: C 62.57H 5.64 N 6.44 Found: 62.68 5.81 6.25 Example 196 · — [ (2-n-Butyl-6- (2-isopropyl-5-methyl-cyclohexyloxycarbonylamino)-benzimidazol-l-yl)-methyl]biphenyl-2carboxylic acid semi-trifluoroacetate Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(2-isopropyl-5-methylcyclohexyloxycarbonylamino) -benzimidazol-l-yl) -methyl)biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 94.1 % of theoretical, Melting point: 149-151 °C 215 C36H„N3O4 X 0.5 CF3COOH (638.77) Calculated: C 69.57 H 6.86 N 6.58 Found: 69.39 6.91 6.56 Example 197 *-[(2-n-Butyl-6-cyclohexylacetamino-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4 1 - [ (2-n-butyl-6-cyclohexylacetaminobenzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Example 198 4(2-n-Butyl-benzimidazol-l-yl)-methyl]biphenyl-2carboxylic acid-(N—benzenesulphonyl)-amide 960 mg (2.5 mmol) of4’-[(2-n-butyl-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid are dissolved in 25 ml of methylene chloride, treated with 2 ml of thionyl chloride and heated under reflux for one hour. The solvent is then distilled off and evaporated 2 times after adding methylene chloride. 390 mg (2.5 mmol) of benzenesulphonamide are added to the residue and the mixture is heated for one hour at 140 °C. After cooling, the oil obtained is taken up in ethyl acetate/sodium chloride solution and extracted 3 times using ethyl acetate. The combined ethyl acetate phases are dried over sodium sulphate, evaporated and the crude product obtained is purified over a silica gel column using methylene chloride/ethanol as eluting agent.
Yield: 0.15 g (11 % of theoretical), Melting point: 131-132 °C 216 C31H29N3O3S (523.65) Calculated: C 71.11 Found: 70.96 H 5.58 5.49 N 8.02 8.21 The following compounds are obtained in analogous manner: ’ — [ (2-n-butyl-6-methoxy-benzimidazol-l-yl) -methyl ] biphenyl-2-carboxylic acid-(N-methanesulphonyl)-amide ’ - [(2-methoxymethyl-benzimidazol-l-yl)-methyl]biphenyl-2 -carboxylic acid-(N-methanesulphonyl)-amide · — [(2-n-pentyl-benzimidazol-l-yl)-methyl]biphenyl-2carboxylic acid-(N-methanesulphonyl)-amide * -((2-n-butyl-4-methyl-7-methoxy-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid-(N-methanesulphonyl)amide 4'-[(2-n-propyl-benzimidazol-l-yl)-methyl}biphenyl-2carboxylic acid-(N-methanesulphonyl)-amide 4’-[(2-n-butyl-5-acetamino-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid-(N-methanesulphonyl)-amide 4·-[(2-n-butyl-5-chloro-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid-(N-methanesulphonyl)-amide 4'-[(2-n-butyl-5-butylaminocarbonylamino-benzimidazol-ly1)-methyl]biphenyl-2-carboxylic acid-(N-methanesulphony1)-amide 4'-[(2-n-butyl-6-phenylaminocarbonylamino-benzimidazoll-yl) -methyl]biphenyl-2-carboxylic acid-(N-methanesulphonyl)-amide 217 4’—[(2-n-buty1-6-cyclohexylaminocarbonylamino-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid-(Nmethanesulphony1)-amide 4(2-n-butyl-5-butanoylamino-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid-(N-methanesulphonyl)amide 4·- ((2-n-butyl-6-chloro-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid-(N-methanesulphonyl)-amide 4’—[(2-n-butyl-5-methanesulphonamino-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid-(N-methanesulphonyl)amide *-[(2-n-butyl-6-ethoxycarbonylamino-benzimidazol-l-yl) methyl]biphenyl-2-carboxylic acid-(N-methanesulphonyl)amide 4'-[(2-n-butyl-6-isopropylsulphonamino-benzimidazol-lyl)-methyl]biphenyl-2-carboxylic acid-(Nmethanesulphonyl)-amide · - [ (2-n-butyl-4-rbutanoylamino-benzimidazOl-l-yl) methyl]biphenyl-2-carboxylic acid-(N-methanesulphonyl)amide 4' -[ (2-n-butyl-6-dimethylamino-benzimidazol-l-yl) methyl]biphenyl-2-carboxylic acid-(N-methanesulphonyl)amide 4' — [ (2-n-butyl-5,6-dimethoxy-benzimidazol-l-yl) -methyl} biphenyl-2-carboxylic acid-(N-methanesulphonyl)-amide 4’-((2-(l-butyn-4-yl)-benzimidazol-l-yl)methyl)biphenyl-2-carboxylic acid-(N-methanesulphonyl)amide 218 4'-[(2-n-butyl-5-and 6-trifluoromethyl-benzimidazol-ly1)-methyl]biphenyl-2-carboxylic acid-(N-methanesulphonyl) -amide '-[ (2-n-butyl-5-and 6-n-butylaminocarbonyl-benzimidazol-l-yl) -methyl] biphenyl-2-carboxylic acid- (N-methanesulphonyl)-amide ’-[ (2-n-butyl-5-dimethylaminosulphonyl-benzimidazol-lyl ) -methyl ] biphenyl-2 -carboxyl ic acid- (N-methanesulphonyl)-amide * - ( (2-n-butyl-7-cyano-benzimidazol-l-yl) -methyl]biphenyl-2-carboxylic acid-(N-methanesulphonyl) -amide (2-n-butyl-6-cyclohexylaminocarbonyl-benzimidazol-lyl) -methyl ] biphenyl-2-carboxylic acid-(N-methanesulphonyl) -amide ’ — [ (2-n-butyl-6-(N-methyl-n-butylaminocarbonyl) -benzimi dazbl-1-yl) -methyl]bipheny 1-2-carboxylic acid- (Nmethanesulphonyl)-amide (2-n-btityl-6-cyciohexylcarbonylamino-benzimidazol-lyl) -methyl]biphenyl-2-carboxylic acid-(Nmethanesulphonyl)-amide 4' - [ (2-n-butyl-6- (N-cyclohexylaminocarbonyl-n-pentylamin o) -benzimidazol-l-yl) -methyl]biphenyl-2-carboxylic acid(N-methanesulphonyl)-amide · - ((6-n-butanoylamino-2-n-butyl-benzimidazol-l-yl) methyl]biphenyl-2-carboxylic acid- (N-methanesulphonyl) amide 219 4'—[(2-n-butyl-6-propionylamino-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid-(N-methane-sulphonyl) amide 4’-[(2-n-butyl-5-(N-methylaminocarbonyl-n-pentylamino)benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid-(N methanesulphonyl)-amide - 4'-[(2-n-butyl-6-(N-(n-butylaminocarbonyl)-methylamino) benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid-(N methanesulphonyl)-amide 4' —[(2-n-butyl-5-(N-propanoyl-methylamino)-benzimidazol 1-yl)-methyl]biphenyl-2-carboxylic acid-(Nmethanesulphony1)-amide 4’-[(2-n-butyl-5-formylamino-benzimidazol-l-yl)methyl]biphenyl-2-carboxylie acid-(N-methane-sulphonyl) amide 41 — [ (2-n-butyl-6-(N-methylaminocarbonyl-n-pentylamino) benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid-(N methanesulphonyl)-amide 4'-[(6-aminothiocarb0nylamino-2-n-butyl-benzimidazol-lyl)-methyl]biphenyl-2-carboxylic acid-(N-methanesulphonyl) -amide 4‘(2-n-butyl-7-methoxy-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid-(N-methanesulphonyl)-amide 4’-[(2-n-buty1-6-cyclohexylmethylaminocarbony135 benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid-(N methanesulphonyl)-amide 220 4'-[(2-n-butyl-6-methoxy-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid-(N-trifluoromethanesulphonyl)-amide — [(2-methoxymethyl-benzimidazol-l-yl)-methylJbipheny 1-2 -carboxylic acid-(N-trifluoromethane-sulphonyl) · amide (2-n-pentyl-benzimidazol-l-yl) -methyl]bi-phenyl-2carboxylic acid-(N-trifluoromethane-sulphonyl)-amide ’ - [ (2-n-butyl-4-methyl-7-methoxy-benzimidazol-l-yl) methyl]biphenyl-2-carboxylic acid-(N-trifluoromethanesulphonyl )-amide 4'-[(2-n-propyl-benzimidazol-l-yl)-methyl]biphenyl-2carboxylic acid-(N-trifluoromethanesulphonyl)-amide * — [ (2-n-butyl-5-acetamino-benzimidazol-l-yl) -methyl]biphenyl-2-carboxylic acid-(N-trifluoromethanesulphonyl) -amide 4’(2-n-butyl-5-chloro-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid-(N-trifluoromethanesulphonyl) -amide ’ - [ (2-n-butyl-5-butylaminocarbonylamino-benzimid-azol1-yl)-methyl]biphenyl-2-carboxylic acid-(Ntrifluoromethanesulphonyl)-amide ·-[ (2-n-butyl-6-phenylaminocarbonylamino-benzimid-azol 1—yl)—methyl]biphenyl—2—carboxylic acid-(Ntri fluoromethanesulphonyl)-amide ·-[ (2-n-butyl-6-cyclohexylaminocarbonylamino-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid-(Ntri fluoromethanesulphonyl)-amide 221 * — [(2-n-buty1-5-butanoylamino-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid-(N-trifluoromethanesulphonyl) -amide 41 — [(2-n-butyl-6-chloro-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid-(N-trifluoromethanesulphonyl)-amide ’ — [ (2-n-butyl-5-methanesulphonamino-benzimidazol-l-yl) methyl]biphenyl-2-carboxylic acid-(N-trifluoromethanesulphonyl )-amide 41-[(2-n-butyl-6-ethoxycarbonylamino-benzimidazol-l-yl) methyl]biphenyl-2-carboxylic acid-(N-trifluoromethanesulphonyl)-amide ’ - [ (2-n-buty 1-6-isopropylsulphonamino-benzimidazol-lyl) -methyl]biphenyl-2-carboxylic acid- (N-trifluoromethanesulphonyl)-amide 4' — [ (2-n-butyl-4-butanoylamino-benz imidazol-l-yl)methylJbiphenyl-2-carboxylic acid- (N-trifluoromethanesulphonyl) -amide 4’-[(2-n-butyl-6-dimethylamino-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid-(N-trifluoromethanesulphonyl)-amide 41-[(2-n-butyl-5,6-dimethoxy-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid-(N-trifluoromethanesulphonyl) -amide 4'—[(2-(l-butyn-4-yl)-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid-(Ntrifluoromethanesulphonyl)-amide 222 4'-[(2-n-butyl-5-and 6-trifluoromethyl-benzimidazol-lyl)-methyl]biphenyl-2-carboxylic acid-(N-trifluoromethanesulphonyl) -amide 4·—((2-n—butyl—5—and 6-n-butylaminocarbonyl-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid-(N-trifluoromethanesulphonyl)-amide 41-[(2-n-butyl-5-dimethylaminosulphonyl-benzimidazol-l10 yl)-methyl]biphenyl-2-carboxylic acid-(N-trifluoromethanesulphonyl) -amide 4’-[(2-n-butyl-7-cyano-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid-(N-trifluoromethane15 sulphonyl)-amide 4‘[(2-n-butyl-6-cyclohexylaminocarbonyl-benzimid-azol1-yl)-methyl]biphenyl-2-carboxylic acid-(Ntrifluoromethanesulphonyl)-amide 4'-[(2-n-butyl-6-(N-methyl-n-butylaminocarbonyl)-benzimi dazol-l-yl)-methylJbiphenyl-2-carboxylic acid-(Ntrifluoromethanesulphonyl)-amide 4'-[(2-n-butyl-6-cyclohexylcarbonylamino-benzimid-azol1-yl)-methyl]biphenyl-2-carboxylic acid-(Ntrifluoromethanesulphonyl)-amide 4'-[(2-n-butyl-6-(N-cyclohexylaminocarbonyl-n-pentylamin o)-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid(N-trifluoromethanesulphonyl)-amide 4(6-n-butanoylamino-2-n-butyl-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid-(N-trifluoromethane35 sulphonyl)-amide 4·-[(2-n-butyl-6-propionylamino-benzimidazol-l-yl)223 methyl]biphenyl-2-carboxylic acid-(N-trifluoromethanesulphonyl)-amide 4(2-n-butyl-5-(N-methylaminocarbonyl-n-pentylamino)benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid-(N trifluoromethanesulphonyl)-amide · -[ (2-n-butyl-6-(N- (n-butylaminocarbonyl) -methylamino) benzimidazol-l-yl) -methyl) biphenyl-2-carboxylic acid- (N θ tri fluoromethanesulphonyl)-amide 4(2-n-butyl-5-(N-propanoyl-methylamino)-benzimidazol 1-yl)-methyl]biphenyl-2-carboxylic acid-(N-trifluoromethanesulphonyl) -amide 41 — [(2-n-butyl-5-formylamino-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid-(N-trifluoromethanesulphonyl )-amide 4 · — [ (2-n-butyl-6- (N-methylaminocarbonyl-n-pentylamino) benz imidazol-l-yl) -methyl ] biphenyl-2-carboxylic acid- (N trif luoromethanesulphonyl)-amide 4’-((6-aminothiocarbonylamino-2-n-butyl-benzimidazol-l25 yl)-methyl)biphenyl-2-carboxylic acid-(Ntr if luoromethanesulphonyl)-amide 41 — [(2-n-butyl-7-methoxy-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid-(N-trifluoromethane3θ sulphonyl)-amide *-[(2-n-butyl-6-cyclohexylmethylaminocarbonylbenzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid-(N trifluoromethanesulphony1)-amide 35 4'-[(2-n-butyl-6-methoxy-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylic acid-(N-benzenesulphonyl)-amide 224 4(2-methoxymethyl-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid-(N-benzenesulphonyl)-amide 4 · — [ (2-n-pentyl-benzimidazol-l-yl) -methyl]biphenyl-2carboxylic acid-(N-benzenesulphonyl)-amide * — [ (2-n-butyl-4-methyl-7-methoxy-benzimidazol-l-yl) methyl]biphenyl-2-carboxylic acid-(N-benzene-sulphonyl)1 θ amide 4(2-n-propyl-benzimidazol-l-yl) -methyl]biphenyl-2carboxylic acid-(N-benzenesulphonyl)-amide 4 ’ — [ (2-n-butyl-5-acetamino-benzimidazol-l-yl) -methyl ] biphenyl-2-carboxylic acid-(N-benzenesulphonyl)-amide 4' - [(2-n-butyl-5-chloro-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid-(N-benzenesulphonyl)-amide · - [ (2-n-butyl-5-butylaminocarbonylamino-benzimidazol-lyl) -methyl]biphenyl-2-carboxylic acid-(N-benzenesulphonyl)-amide 4 · - [ (2-n-butyl-6-phenylaminocarbonylamino-benzimidazol1-yl) -methyl]biphehyl-2-carboxylic acid-(Nbenzenesulphonyl)-amide · — ( ( 2-n-butyl-6-cyclohexylaminocarboriylamino30 benz imidazol-l-yl)-methyl] biphenyl-2-carboxylic acid-(Nbenzenesulphonyl)-amide 4'-[(2-n-butyl-5-butanoylamino-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid-(N-benzenesulphonyl) 35 amide (2-n-butyl-6-chloro-benzimidazol-l-yl)-methyl] 225 biphenyl-2-carboxylic acid-(N-benzenesulphonyl)-amide ’-[ (2-n-butyl-5-methanesulphonamino-benz imidazol-l-yl) methyl]biphenyl-2-carboxylic acid- (N-benzene-sulphonyl) amide 4'-[ (2-n-butyl-6-ethoxycarbonylamino-benz imidazol-l-yl) methyl ]biphenyl-2-carboxylic acid- (N-benzene-sulphonyl) amide 4' — [ (2-n-butyl-6-isopropylsulphonamino-benzimidazol-lyl) -methyl ] biphenyl-2-carboxylic acid- (N-benzenesulphonyl) -amide 4 '-[ (2-n-butyl-4-butanoylamino-benzimidazol-l-yl) methyl]biphenyl-2-carboxylic acid- (N-benzene-sulphonyl) amide — [ (2-n-butyl-6-dimethylamino-benzimidazol-l-yl) 2Q methyl]biphenyl-2-carboxylic acid-(N-benzene-sulphonyl) amide 4*—[(2—ή—butyl—5,6—dimethoxy—benzimidazol—1-yl)— methyl)biphenyl-2-carboxylic acid-(N-benzene-sulphonyl) amide 4'-[(2-(l-butyn-4-yl)-benzimidazol-l-yl)methyl ] biphenyl-2-carboxylic acid- (N-benzenesulphonyl) amide 4·—((2-n-butyl-5-and 6-trifluoromethyl-benzimidazol-lyl)-methyl]biphenyl-2-carboxylic acid-(N-benzenesulphonyl) -amide 41—[(2—n—butyl—5-and 6-n-butylaminocarbonyl-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid-(N-benzene sulphonyl)-amide 226 ·-[ (2-n-butyl-5-dimethylaminosulphonyl-benzimidazol-lyl)-methyl]biphenyl-2-carboxylic acid-(Nbenzenesulphonyl)-amide 41 -[ (2-n-butyl-7-cyano-benzimidazol-l-yl) -methyl]biphenyl-2-carboxylic acid-(N-benzenesulphonyl)-amide ’ — [ (2-n-butyl-6-cyclohexylaminocarbonyl-benzimid-azol1-yl)-methyl]biphenyl-2-carboxylic acid-(Nbenzenesulphonyl)-amide 4(2-n-butyl-6-(N-methyl-n-butylaminocarbonyl) -benzimi dazol-l-yl)-methyl]biphenyl-2-carboxylic acid-(Nbenzenesulphonyl)-amide 4(2-n-butyl-6-cyclohexylcarbonylamino-benzimid-azol1-yl)-methyl ] biphenyl-2-carboxylic acid-(Nbenzenesulphonyl)-amide 4' - [ (2-n-butyl-6- (N-cyclohexylaminocarbonyl-n-pentylamin o) -benzimidazol-l-yl) -methyl ] biphenyl-2-carboxylic acid(N-benzenesulphonyl)-amide 4' -( (6-n-butanoylamino-2-n-butyi-benzimidazol-l-yl) methyl ] biphenyl-2-carboxylic acid- (N-benZene-sulphonyl) amide ’ - ((2-n-butyl-6-propionylamino-benzimidazol-l-yl) methyl]biphenyl-2-carboxylic acid-(N-benzene-sulphonyl)amide 4' - [ (2-n-butyl-5- (N-methylaminocarbonyl-n-pentylamino) benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid-(Nbenzenesulphonyl)-amide ' - [ (2-n-butyl-6- (N- (n-butylaminocarbonyl) -methylamino) 227 benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid-(Nbenzenesulphonyl)-amide 4'-[(2-n-butyl-5-(N-propanoyl-methylamino)-benzimidazol5 1-yl)-methyl]biphenyl-2-carboxylic acid-(N-benzenesulphonyl)-amide 4’-[(2-n-butyl-5-formylamino-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid-(N-benzenesulphonyl)10 amide ' - [ (2-n-butyl-6- (N-methylaminocarbonyl-n-pentylamino) benzimidazol-l-yl) -methyl]biphenyl-2-carboxylic acid- (Nbenzenesulphonyl)-amide *·-( (6-aminothiocarbonylamino-2-n-butyl-benzimidazol-lyl) -methyl]biphenyl-2-carboxylic acid-(Nbenzenesulphonyl)-amide 4 · - [ (2-n-butyl-7-methoxy-benzimidazol-l-yl) -methyl ] biphenyl-2-carboxylic acid- (N-benzenesulphonyl) -amide ’ - [ (2-n-butyl-6-cyclohexylmethylaminocarbonylbenzimidazol-l-yi)-methyl]biphenyl-2-carboxylic acid-(N25 benzenesulphonyl)-amide Example 199 4'-[(2-n-Butyl-6-formylamino-benzimidazol-l-yl)30 methyl]biphenyl-2-carboxylic acid x 0.75 trifluoroacetic acid Prepared in analogous manner to Example 9 from 35 tert.butyl 4'-[(2-n-butyl-6-formylamino-benzimidazol-1 y 1) -methyl J biphenyl -2 -carboxyl ate and trif luoroacetic acid. 228 Yield: 84.0 % of theoretical, Melting point: 110-112 °C (amorphous) C33H37N3O3 X 0.75 CF3COOH (513.02) Calculated: C 64.38 H 5.06 N 8.19 Found: 64.70 5.25 7.91 Example 200 ’ - [(2-n-Butyl-6-(N-cyclohexylaminocarbonylcyclohexy lamino) -benzimidazol-l-yl) -methyl]biphenyl-2carboxylic acid semi-trifluoroacetate Prepared in analogous manner to Example 9 from tert. butyl 4 ’ - [ (2-n-butyl-6- (N-cyclohexylaminocarbonylcyclohexylamino) -benzimidazol-l-yl) -methyl ]biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 91.9 % of theoretical.
Melting point: 130-132 °C (amorphous) C38H46N4O3 X 0.5 CF3COOH (663.82) Calculated: C 70.57 H 7.06 N 8.44 Found: 70.48 7.13 8.60 Example 201 4(2-n-Butyl-6-(N-(n-butylaminocarbonyl) -cyclohexylami no)-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4·-[(2-n-butyl-6-(N-(n-butylaminocarbonyl)cyclohexylamino) -benzimidazol-l-yl)-methyl]biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 85.7 % of theoretical.
Melting point: 227-228 °C C38H„N4O3 (580.77) calculated: C 74.45 H 7.64 N 9.65 229 Found: 74.32 7.70 9.50 Example 202 ’ — [(2-n-Butyl-6-(N-methylaminocarbonyl-cyclohexylamino)-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4’-[(2-n-butyl-6-(N-methylaminocarbonylcyclohexylamino)-benzimidazol-l-yl)-methyl]biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 88.3 % of theoretical, Melting point: 204-206 °C C33H38N4O3 (538.69) Calculated: C 73.58 H 7.11 N 10.40 Found: 73.65 6.99 10.49 Example 203 4(2-n-Butyl-6-(M-ethoXycarbonyl-cyclohexylamino)benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4·-[(2-n-butyl-6-(N-ethoxycarbonylcyclohexyl-amino)-benzimidazol-l-yl)-methyl]biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 89.0 % of theoretical, Melting point: 239-240 °C C„H39N3O4 (553.70) Calculated: C 73.75 H 7.10 N 7.59 Found: 73.76 7.25 7.68 Example 204 230 4'-((2-n-Butyl-6-cyclohexylacetamino-benzimidazol-l-yl)methyl]biphenyl-2-carboxylie acid x 0.7 trifluoroacetic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-ri-butyl-6-cyclohexylacetaminobenzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 97.5 % of theoretical, Melting point: 117-119 °C C33H37N3O3 X 0.7 CF3COOH (603.49) Calculated: C 68.46 H 6.30 N 6.96 Found: 68.80 6.60 6.73 Example 205 (2-n-Butyl-6-phthalimino-benzimidazol-l-yl) methyl ]biphenyl-2-carboxylic acid semi-trifluoroacetate Prepared in analogous manner to Example 9 from tert.butyl 41-[(2-n-butyl-6-phthalimino-benzimidazol-lyl) -methyl ] biphenyl-2 -carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 85.5 % of theoretical, Melting point: 181-183 °C C33H27N3O4 x 0.5 CF3COOH (586.61) Calculated: C 69.62 H 4.73 N 7.16 Found: 69.70 4.81 7.31 231 Example 206 4·—[(2-n-Butyl-6-((5-trifluoroacetoxy-n-pentyl)aminocarbonylamino)-benzimidazol-l-yl)-methylJbiphenyl2-carboxylic acid semi-trifluoroacetate semi-hydrate ϊθ 1.92 g (3.3 mmol) of tert.butyl 4·-[(2-n-butyl-6(tetrahydropyran-2-yl-aminocarbonylamino)-benz imidazol1- yl)-methyl ]biphenyl-2-carboxylate are dissolved in 100 ml of ethanol and 1.9 g of Raney nickel is added. The reaction solution is then hydrogenated for 4 hours at 120 °C and 100 bar hydrogen. Catalyst is then filtered off under suction and the solvent is distilled off in vacuum. The oily residue is purified over a column (silica gel; grain size: 0.063-0.2 mm), the column being eluted using methylene chloride and increasing parts of 2- 5 % ethanol. After rotary evaporation of the appropriate fractions, the oil obtained is dissolved in a mixture of 10 ml of methylene chloride and 10 ml of trifluoroacetic acid, and the solution is left for 15 hours at ambient temperature. The solvent is removed by rotary evaporation, the residue is dissolved in about 50 ml of ethyl acetate and the organic phase is washed 3 times using about 50 ml of water. The organic solution is dried using about 20 g of magnesium sulphate, filtered off and rotary evaporated. The product thus obtained is dried at 50 °C in vacuum. 232 Yield: 1.5 g (66.0 % of theoretical), Melting point: 80-82 °C (amorphous) Calculated: C 59.13 H 5.33 N 8.11 Found: 59.22 5.52 7.95 Example 207 '-[ (2-n-Butyl-6-(N-ethoxycarbonyl-benzylamino) benz imidazol-l-yl) -methyl ] biphenyl-2 -carboxyl ic acid Prepared in analogous manner to Example 9 from tert.butyl 4·-[(2-n-butyl-6-(N-ethoxycarbonylbenzylamino)-benzimidazol-l-yl) -methyl]biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 86.4 % of theoretical, Melting point: 218-220 °C C35H35N3O4 (561.68) Calculated: C 74.84 H 6.28 N 7.48 Found: 74.57 6.14 7.59 Example 208 4' - [ (2-n-Butyl-6- (N-methylaminocarbonyl-benzylamino) benzimidazol-l-yl) -methyl] biphenyl-2 -carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4’(2-n-butyl-6-(N-methylaminocarbonylbenzylamino)-benzimidazol-l-yl)-methyl]biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 83.3 % of theoretical, Melting point: 247-249 °C C„H34N,O3 (546.67) Calculated: C 74.70 H 6.27 N 10.25 Found: 74.95 6.37 10.12 233 Example 2ng 4'-[(2-n-Butyl-6-(n-hexyloxycarbonylamino)-benzimidazoll-yl) -methyl]biphenyl-2-carboxylic acid 5 Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(n-hexyloxycarbonylamino)benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 89.5 % of theoretical, Melting point: 243-244 °C C32H37N3O4 (527.66) Calculated: C 72.84 H 7.07 N 7.96 Found: 72.65 7.15 7.98 Example 210 4'-[(2-n-Butyl-6-(M-(n-hexylaminocarbony1)-benzylamino)benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4’-[(2-n-butyl-6-(N-(n-hexylaminocarbony1)benzylamino) -benzimidazol-l-yl) -methyl ]biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 69.2 % of theoretical.
Melting point: 186-187 °C C39H„N4O3 (616.80) Calculated: C 75.94 H 7.19 N 9.08 Found: 75.85 7.24 9.14 234 Example 211 4' — [ (2-n-Butyl-6-(n-pentylamino) -benzimidazol-l-yl) methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert. butyl 4' - [ (2-n-butyl-6- (n-pentylamino) -benzimidazol-l-yl) -methyl]biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Yield: 75 % of theoretical, Melting point: 108-113 °C C30H35N3O2 (469.62) Calculated: C 76.73 H 7.51 N 8.94 Pound: 76.56 7.40 8.91 Example 212 41 -[ (2-n-Butyl-6.- (5,7-dioxo-lH, 3H-imidazo[ 1,5-c]thiazol6-yl) -benzimidazol-l-yl) -methyl] biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4’-((2-n-butyl-6-(5,7-dioxo-lH,3H-imidazo[1,5-c] thiazol-6-yl) -benzimidazol-l-yl) -methyl] bipheny 12-carboxylate and trifluoroacetic acid.
Yield: 95.1 % of theoretical, Melting point: 229-230 °C CjAiW (540.64) Calculated: C 66.65 H 5.22 N 10.36 S 5.93 Found: 66.42 5.29 10.15 6.01 Example 213 4' - [ (2-n-Butyl-6- ((5-hydroxy-n-pentyl) -aminocarbonylamin 235 o)-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid monohydrate Prepared in analogous manner to Example 72 from ethyl 4 1 — [ (2-n-butyl-6-((5-hydroxy-n-penty 1) -aminocarbonylamino) -benzimidazol-l-yl) -methyl ] biphenyl-2-carboxy late and 2N NaOH/ethanol.
Yield: 50.0 % of theoretical, Melting point: 158-160 °C C31H36N4O4 X H20 ( 546.67) Calculated: C 68.11 H 7.01 N 10.25 Found: 68.01 6.90 10.30 Example 214 Ethyl 4'—[(2-n-butyl-6-((5-hydroxy-n-pentyl)aminocarbonyl-amino) -benzimidazol-l-yl) -methyl ] biphenyl2-carboxylate __ . 7.5 g (13.5 mmol) of ethyl 4’-[ (2-ri-butyl-6-(tetrahydro-pyran-2-ylaminocarbonylamino, -benzimidazol-l-yl) methyl]biphenyl-2-carboxylate are dissolved in 250 ml of ethanol and 7.5 g of Raney nickel are added. The solution is then hydrogenated in an autoclave for 2 hours at 120 °C and 100 bar of hydrogen. The catalyst is then filtered off under suction and the solvent is distilled off in vacuum. The oily product obtained is purified over a column (silica gel; grain size: 0.0630.2 mm), the column being eluted using ethyl acetate/petroleum ether (9/1) and using ethyl acetate/ethanol (99/1). The appropriate fractions are evaporated in vacuum and dried at 50 °C in a vacuum, drying oven.
Yield: 2.6 g (34.7 % of theoretical), oil, Rf: 0.50 (silica gel: ethyl acetate/ethanol = 9:1) 236 Example 215 · — [ (2-n-Butyl-6-(N— (n-butanoyl) -n-butylamino) -benzimida zol-l-yl)-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4(2-n-butyl-6-(N-(n-butanoyl)-n-butylamino) -benzimidazol-l-yl) -methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 90.6 % of theoretical, Melting point: 234-235 °C C33H3gN3O3 (525.69) Calculated: C 75.40 H 7.48 N 7.99 Found: 75.55 7.49 8.02 Example 216 4(2-n-Butyl-6-(N-(4-methoxycarbonyl-thiazolidin-3-ylcarbonyl) -n-butylamino) -benzimidazol-l-yl) -methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4 ’ -((2-n-butyl-6-(N-(4-methoxycarbonylthiazolidin-3-ylcarbonyl) -n-butylamino) -benzimidazol-lyl)-methyl ]hiphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 92.6 % of theoretical, Melting point: 86-88 °C (amorphous) C35H40N4O5S (628.79) Calculated: C 66.86 H 6.41 N 8.91 S 5.10 Found: 66.68 6.40 8.50 5.41 237 Example 217 41-[(2-n-Butyl-6-(N-cyclohexylaminocarbonyl-n-butylamino) -benzimidazol-l-yl) -methyl] biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 41-[(2-n-butyl-6-(N-cyclohexylaminocarbonyln-butylamino) -benzimidazol-l-yl) -methyl] biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 96.8 % of theoretical, Melting point: 106-108 °C (amorphous) C36H„N,O3 (580.77) Calculated: C 74.45 H 7.64 N 9.65 Found: 74.54 7.65 9.50 Example 218 ' - [ (2-n-Butyl-6- (N-cyclohexylaminocarbonyl-benzylamino) -benzimidazol-l-yl) -methyl] biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-cyclohexylaminocarbonylbenzylamino) -benzimidazol-l-yl) -methyl] biphenyl-2carboxylate.
Yield: 95.0 % of theoretical, Melting point: 203-204 °C C39HA2N,O3 (614.79) Calculated: C 76.19 H 6.89 N 9.11 Found: 75.93 7.04 9.34 238 Example 219 4'-((2-n-Butyl-6-(N-(2-trif luoromethylphenylaminocarbonyl) -methylamino) -benzimidazol-l-yl) -methyl ] biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4·-[(2-n-butyl-6-(N-(2-trifluoromethyIphenylaminocarbonyl) -methylamino) -benzimidazol-l-yl) -methyl]biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Yield: 72.2 % of theoretical.
Melting point: 142-144 °C C34H31F3N4O3 X CF3COOH (714.67) Calculated: C 60.52 H 4.51 N 7.84 Found: 60.53 4.48 8.03 Example 220 4·-[(2-n-Butyl-6-(N-cyclohexylaminOcarbonyl-n-hexylamino) -benzimidazol-l-yl) -methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4·-[(2-n-butyl-6-(N-cyclohexylamino-carbonyln-hexyl amino) -benzimidazol-l-yl) -methyl] -bipheny 1-2carboxylate and trifluoroacetic acid.
Yield: 94.1 % of theoretical, Melting point: 177-178 °C C38H48N,O3 (608.82) Calculated: C 74.97 H 7.95 N 9.20 Found: 74.75 8.04 9.09 Example 22l 239 4' — [(2-n-Butyl-6-(N-cyclohexylcarbonyl-n-hexylamino)benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4' - [(2-n-buty1-6-(N-cyclohexylcarbonyl-n hexylamino)-benzimidazol-l-yl)-methyl]biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 92.8 % of theoretical, Melting point: 195-197 °C C38H„N3O3 (593.81) Calculated: C 76.86 H 7.98 N 7.08 Found: 76.66 7.94 7.16 Example 222 4(2-n-Butyl-6-(N-cyclohexylaminocarbonyl-n-propylamin o) -benzimidazol-l-yl) -methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4·-[(2-n-butyl-6-(N-cyclohexylaminocarbonyln-propylamino) -benzimidazol-l-yl) -methyl ] biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 93.5 % of theoretical, Melting point: 180-182 °C C35HA2N4O3 (566.74) Calculated: C 74.18 H 7.47 N 9.89 Found: 73.98 7.54 10.05 Example 223 4’-[(2-n-Butyl-6-(N-cyclohexylcarbonyl-methylamino)benz imidazol-l-yl) -methyl ] biphenyl-2-carboxylic acid semi-hydrate Prepared in analogous manner to Example 9 from 240 tert.butyl 4'-[(2-n-butyl-6-(N-cyclohexylcarbonylmethylamino)-benzimidazol-l-yl)-methyl]biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 93.8 % of theoretical, Melting point: 230-231 °C C33H37N3O3 x 0.5 H2O (532.68) Calculated: C 74.41 H 7.19 N 7.89 Found: 74.59 7.14 7.70 Example 224 4’-[(2-n-Butyl-6-(N-cyclohexylaminocarbonyl-ethylamino)-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 41-[(2-n-butyl-6-(N-cyclohexylaminocarbonylethylamino) -benzimidazol-l-yl)-methyl]biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 95.5 % of theoretical, Melting point: 185-186 °C C34H40N4O3 (552.72) Calculated: C 73.89 H 7.29 N 10.14 Found: 73,79 7.13 10.11 Example 225 · - [(2-n-Butyl-6-(N-(n-butanoyl)-n-pentylamino)-benzimid azol-l-yl)-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4’-[(2-n-butyl-6-(N-(n-butanoyl)-n-pentylamino)-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 77.8 % of theoretical, 241 Melting point: 206-208 °C C34H41N3O3 (539.72) Calculated: C 75.66 Found: 75.54 H 7.66 7.47 N 7.79 7.67 Example 226 (2-n-Butyl-6-isopropylcarbonylamino-benzimidazol-lyl) -methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-isopropylcarbonylaminobenz imidazol-l-yl) -methyl] biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 73.3 % of theoretical, Melting point: 273-275 °C C29H31N3O3 (469.58) Calculated: C 74.18 H 6.65 N 8.95 Found: 73.93 6.66 8.84 Example 22 7 ’ — [ (2-n-Butyl-6- (N-ethoxycarbonyl-methylamino) benzimidazol-l-yl) -methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4’-[(2-n-butyl-6-(N-ethoxycarbonylmethylamino)-benzimidazol-l-yl)-methyl]biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 91.8 % of theoretical, Melting point: 190-192 °C C29H31N3O4 (485.58) Calculated: Found: C 71.73 H 6.43 N 8.65 71.60 6.40 8.69 242 Example 228 · - [ (2-n-Butyl-6-(N-ethoxycarbonyl-n-pentylamino) -benzim idazol-l-yl)-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert. butyl 4 · - [ (2-n-butyl-6- (N-ethoxycarbonyl-n-pentylamino) -benzimidazol-l-yl) -methyl]biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Yield: 86.9 % of theoretical, Melting point: 201-203 °C C33H39N3O, (541.69) Calculated: C 73.17 H 7.26 N 7.76 Found: 72.97 6.98 7.69 Example 229 4’-[(2-n-Butyl-6-(N-(dimethylaminocarbonyl)benzylamino) -benzimidazol-l-yl) -methyl ]biphenyl-2carboxylic acid Prepared in analogous manner to Example 9 from tert .butyl 4 * - [ (2-n-butyl-6- (N- (dimethyl aminocarbonyl) benzylamino) -benzimidazol-l-yl) -methyl ] biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 75.3 % of theoretical, Melting point: 202-203 °C C3SH36N4O3 (560.69) Calculated: C 74.98 H 6.47 N 9.99 Found: 74.89 6.24 10.02 243 Example 23Ο 4' — [ (2-n-Butyl-6- (N-cyclohexylaminocarbonyl-N- (2-phenyle thyl) -amino) -benzimidazol-l-yl) -methyl] bipheny 1-2carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4 *-[(2-n-butyl-6-(N-cyclohexylaminocarbonylN- (2-pheny lethyl) -amino) -benzimidazol-l-yl) -methyl Jbiphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 70.0 % of theoretical, Melting point: 168-170 °C Ca0H„N4O3 (628.81) Calculated: C 76.40 H 7.05 N 8.91 Found: 76.31 7.26 8.79 244 Example 231 · —[ (2-n-Butyl-6-diethylaminocarbonylamino-benzimidazol1-yl)-methyl]biphenyl-2-carboxylic acid semitr i fluoroacetate Prepared in analogous manner to Example 9 from tert. butyl 4' - [ (2-n-butyl-6-diethylaminocarbonylaminobenzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 79.4 % of theoretical, Melting point: 235-237 °C C30H34N4O3 X 0.5 CF3COOH (555.64) Calculated: C 67.01 H 6.26 N 10.08 Found: 66.99 6.02 10.12 Example 232 4(2-n-Butyl-6-dimethylaminoacetamino-benzimidazol-lyl)-methyl]biphenyl-2-carboxylic acid ditrifluoroacetate Prepared in analogous manner to Example 9 from tert.butyl 4 ’-[ (2-n-butyl-6-(dimethylaminoacetamino)benzimidazoi-l-yl) -methyl]biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Yield: 75.5 % of theoretical, Melting point: 218-220 °C C29H32N4O3 x 2 CF3COOH (712.65) Calculated: C 55.61 H 4.81 N 7.86 Found: 55.61 5.05 8.19 245 Example 233 *-[(2-n-Butyl-6-(2,2-dimethyl-propionylamino)-benzimidazol-l-yl) -methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(2,2-dimethylpropionylamino) -benzimidazol-l-yl)-methyl]biphenyl-2carboxylate and trifluoroacetic acid.
Yield: 67.5 % of theoretical, Melting point: 326-327 °C C3qH33N3O3 (483.61) Calculated: C 74.51 H 6.88 N 8.69 Found: 74.32 7.06 8.58 Example 234 4(2-n-Buty1-6-(N-(n-hexylaminocarbonyl)-N-(2-phenylet hyl)-amino)-benzimidazol-l-yl)-methyl]biphenyl-2carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4’-[(2-n-butyl-6-(N-(n-hexylaminocarbonyl)-N(2-phenylethyl)-amino)-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 66.7 % of theoretical, Melting point: 176-177 °C CA0H46N4O3 (630.83) Calculated: C 76.16 H 7.35 N 8.88 Found: 75.97 7.44 8.98 246 Example 235 · - [ (2-n-Butyl-6-cyclopentylcarbonylamino-benzimidazoll-yl)-methyl ]biphenyl-2-carboxylic acid semi-hydrate Prepared in analogous manner to Example 9 from tert. butyl 4 · - [ (2-n-butyl-6-cyclopentylcarbonylaminobenz imidazol-l-yl) -methyl ] biphenyl-2 -carboxylate and trifluoroacetic acid.
Yield: 72.2 % of theoretical, Melting point: 272-274 °C C31H33N3O3 x 0.5 H2O (504.63) Calculated: C 73.79 H 6.79 N 8.33 Found: 74.00 6.91 8.25 Example 236 ’ —[(2-n-Butyl-6-cyclopropylcarbonylamino-benzimid-azol5 1-yl)-methyl]biphenyl-2-carboxylic acid semi-hydrate Prepared in analogous manner to Example 9 from tert.butyl 4·-[(2-n-buty1-6-cyclopropylcarbonylamino10 benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 91.7 % of theoretical.
Melting point: 275-277 °C C28H29N3O3 X 0.5 H20 (476.57) Calculated: C 73.09 H 6.34 N 8.82 Found: 72.97 6.50 8.52 Example 237 4 *-[(2-n-Butyl-6-(l-oxo-isoindolin-2-yl)-benzimidazol-lyl) -methyl]biphenyl-2-carboxylic acid trifluoroacetate '1.6 g (3 mmol) of 4'-[(2-n-butyl-6-phthaliminobenzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid trifluoroacetate are treated with 1.6 g of zinc powder in 30 ml of glacial acetic acid under reflux. After every hour, 1.6 g.of zinc powder are added and heated at reflux for one hour, this takes place 2 times. Excess zinc is filtered off under suction and the filtrate is rotary evaporated to dryness. The crude product is purified over a silica gel column (grain size: 0.063-0.2 mm) using ethyl acetate/ethanol/ammonia (90:10:0.1 to 80:20:0.1) and crystallised from ether.
Yield: 0.45 g (64.1 % of theoretical), Melting point: 214-216 °C C33H2gN3O3 X CF3COOH (629.64) Calculated: C 66.76 H 4.80 N 6.67 248 Found: 66.62 5.08 6.69 Example 238 ' -[ (2- (1-trans-Butenyl) -6-dimethylaminocarbonylaminobenzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid tri fluoroacetate a) Tert.butyl 4·-[(2-(1-bromobutyl)-6-phthaliminobenzimidazol-l-vll -methvnbiphenvl-2-carboxylate .3 g (17.6 mmol) of tert.butyl 4'-[(2-n-butyl-6phthalimino-benzimidazol-l-yl)-methyl]biphenyl-2carboxylate, 1 litre of carbon tetrachloride and 3.1 g (17.5 mmol) of N-bromosuccinimide are irradiated using a mercury immersion lamp for 3 hours while stirring. As a result of this, the internal temperature increases to 50 °C. The greasy product obtained is then filtered off, the residue is dissolved in methylene chloride and extracted by shaking using water. The organic phase is dried over sodium sulphate and rotary evaporated. The crude product is purified over a silica gel column (grain size: 0.0630.2 mm) ethyl acetate/petroleum ether (1:4).
Yield: 4.5 g (38.4 % of theoretical), b) Tert.butyl 4 · -[(2-(1-trans-butenyl)-6-phthaliminobenzimidazol-l-yl 1 -methvl 1 biphenvl-2-carboxvlate .8 g (16.25 mmol) of tert.butyl 4·—[(2-(1-bromobutyl)6-phthalimino-benzimidazol-l-yl)-methyl]biphenyl-2carboxylate, 110 ml of dimethyl formamide and 5.1 ml (5.2 g = 34.1 mmol) of l,8-diazabicyclo[5.4.0]undec-7-ene are stirred overnight at ambient temperature. The mixture is diluted using 200 ml of ether and extracted by shaking using 2N hydrochloric acid and water. The combined acid phase is extracted by shaking using ethyl acetate. The ethyl acetate phase is dried over sodium sulphate and. 249 after rotary evaporation, is purified over a silica gel column (grain size: 0.063-0.2 mm) using ethyl acetate/petroleum ether (20:80 to 30:70). The product crystallises out on evaporation of the appropriate fractions- The product is filtered under suction and washed using ether.
Yield: 2.30 g (24.2 % of theoretical), Melting point: 232-234 °C C37H33N3OA (583.69) Calculated: C 76.14 H 5.70 N 7,20 Found: 75.92 5.69 7.34 c) Tert. butyl 4' - [ 6-amino- (2- (1-trans-butenyl) -benzimidazol-l-vll-methyl1biphenvl-2-carboxylate 2.3 g (3.94 mmol) of tert.butyl 4'-[(2-(1-transbutenyl) -6->phthalimino-benzimidazol-l-yl) -methyl] biphenyl —2-carboxylate, 80 ml of ethanol and 25 ml of 40 % strength aqueous methylamine are stirred for 3 hours at ambient temperature. The mixture is heated for 1/4 hour on a steam bath, cooled and rotary evaporated. The residue is suspended in acetone, cooled and undissolved N-methyl-phthalimide is filtered off. The filtrate is evaporated to dryness.
Yield: 1.78 g (100 % of theoretical).
Melting point: 174-176 °C d) Tert.butyl 4'-[(2-(1-trans-butenyl)-6-dimetbylaminocarbonylamino-benzimidazol-l-yl)-methyl]biphenyl-2carboxvlate Prepared in analogous manner to Example 8 from tert.butyl 4‘-[6-amino-(2-(1-trans-butenyl)-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and dimethylcarbamoylchloride.
Yield: 82.8 % of theoretical, oil, Rf value: 0.35 (Silica gel; methylene 250 chloride/ethanol = 19:1) e) 41 — [(2-(1-trans-Butenyl)-6-dimethylaminocarbonylamino-benz imidazol-l-yl) -methyl ] biphenyl-2-carboxylic acid tri fluoroacetate Prepared in analogous manner to Example 9 from tert. butyl 41 - [ (2- (1-trans-butenyl) -6-dimethylaminocarbonylamino-benzimidazol-l-yl) -methyl) biphenyl-2carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 66.6 % of theoretical, Melting point: 221-223 °C C28H28N4O3 X CF3COOH X 0.5 H2O (591.59) Calculated: C 60.90 H 5.11 N 9.47 Found: 60.83 4.96 9.53 Example 239 4'-[(2-(1-trans—Butenyl)-6-cyclohexylaminocarbonylamino-benz imidazol-l-yl) -methyl ] biphenyl-2-carboxylic acid trifluoroacetate Prepared in analogous manner to Example 238 from 251 tert.butyl 41 — [(2-(l-trans-butenyl)-6-cyclohexylaminocarbonylamino-benzimidazol-l-yl) -methyl]bipheny1-2carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 93.7 % of theoretical, Melting point: 171-173 °C C32H34N4O3 X CF3COOH (636.67) Calculated: C 64.14 H 5.54 N 8.80 Found: 64.00 5.49 8.97 Example 240 Tert.butyl 41-[(2-n-butyl-6-(cis-hexahydrophthalimino)benzimidazol-l-yl) -methyl ]biphenyl-2-carboxylate 1.8 g (4 mmol) of tert.butyl 4'(6-amino-2-n-butylbenzimidazol-l-yl) -methyl]biphenyl-2-carboxylate, 30 ml of glacial acetic acid and 1.85 g (1.2 mmol) of ciscyclohexane-1, 2-dicarboxylic acid anhydride are heated at reflux for one hour with stirring. The reaction mixture is evaporated to dryness. The residue is dissolved in methylene chloride, washed until neutral using saturated sodium bicarbonate solution, dried over sodium sulphate and rotary evaporated. The crude product is purified over a silica gel column (grain size: 0.0630.2 mm) using ethyl acetate/petroleum ether (10:90; :80 and 30:70).
Yield: 1.5 g (64.1 % of theoretical), C37H„N30a (591.80) Calculated: C 75.10 H 6.98 N 7.10 Found: 74.92 7.10 6.99 The following compounds are obtained in analogous manner: tert.butyl 4’-[(2-n-butyl-6-(4,5-dimethyl-l,2,3,6tetrahydrophthalimino) -benzimidazol-l-yl) -methyl] biphenyl- 252 2-carboxylate oil, Rf value: 0.30 (Silica gel; ethyl acetate/petroleum ether = 1:1) tert.butyl 4'-[(2-n-butyl-6-(3,4-dimethoxy-phthalimino)benzimidazol-l-yl) -methyl] biphenyl-2-carboxy late Yield: 33.8 % of theoretical, Melting point: 238-239 °C tert. butyl 4 * - ((2-n-butyl-6- (cis-hexahydrophthalimino) benzimidazol-l-yl)-methyl ]biphenyl-2-carboxylate oil, R£ value: 0.45 (Silica gel: ethyl acetate/petroleum ether = 4:1) ’ — [ (2-n-butyl-6- (cis-hexahydrophthalimino) benzimidazol-l-yl) -methyl ] -2- (1-triphenylmethy1tetrazol-5-yl)-biphenyl oil, Rf value: 0.55 (Silica gel: ethyl acetate/petroleum ether/ammonia = 80:20:1) tert.butyl 4’-[ (2-n-butyl-6-(endo-bicyclo[2.2.2]oct-5ene-2,3-dicarboxylic acid-imino) -benzimidazol-l-yl) methyl]biphenyl-2-carboxylate M.p.: 180-182.5’C tert. butyl 4 ’ - [ (2-n-butyl-6- (cis-hexahydrophthalimino) benzimidazol-l-yl) -methyl ] biphenyl-2-carboxylate oil, Rf value: 0.43 (Silica gel: ethyl acetate/petroleum ether = 2:1) tert.butyl 4·-[(2-n-buty1-6- (methyl-5-norbornene-2,3dicarboxylic acid-imino) -benzimidazol-l-yl) -methyl ] biphenyl-2-carboxylate tert. butyl 4 · - [ (2-n-butyl-6- (trans-hexahydrophthal 253 imino)-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate M.p.: 168-170’C tert.butyl 4'-[(2-n-butyl-6-(3,6-endoxo-l,2,3,65 tetrahydrophthalimino)-benzimidazol-l-yl)-methyl]bipheny 1-2-carboxylate tert.butyl 4’-[(2-n-butyl-6-(cis-5-norbornene^endo-2,3dicarboxylic acid-imino)-benzimidazol-l-yl)-methyl]biphenyl-2 -carboxylate M.p.: 179-180*C 4' - [ (2-n-butyl-5- (N-cyclohexylaminocarbonyl methylamino) -benzimidazol-l-yl) -methyl] -2-(1triphenylmethyl -1etrazol - 5 -yl) -biphenyl Oil, Rf value: 0.45 (silica gel; ethyl acetate/petroleum ether/ammonia = 90:10:1) 4' - ((2-n-butyl-5- (cis-hexahydrophthalimino) benzimidazol-l-yl)-methyl]-2-(1-triphenylmethyl20 tetrazol-5-yl)-biphenyl Oil, Rf value: 0.35 (silica gel: ethyl acetate/petroleum ether =4:1) Example 241 1-[(2-n—Butyl—6—(cis—hexahydrophthalimino) — benzimidazol-l-yl) -methyl ] biphenyl-2-carboxylic acid trifluoroacetate Prepared in analogous manner to Example 9 from tert. butyl 4' — [ (2-n-butyl-6- (cis-hexahydrophthalimino) benzimidazol-l-yl) -methyl] biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 58.8 % of theoretical.
Melting point: 270 °C (decomposition) C33H33N3O4 X CF3COOH (649.68) Calculated: C 64.71 H 5.28 N 6.47 Found: 64.76 5.41 6.65 254 Example 242 ' - [ (2-n-Butyl-6- (4,5-dimethyl-l, 2,3,6-tetrahydrophthali mino) — benzimidazol-l—yl) -methyl] biphenyl—2— carboxylic acid hydrate Prepared in analogous manner to Example 9 from tert. butyl 4 * - [ (2-n-butyl-6- (4,5-dimethyl-l ,2,3,6-i-tetrahydrophthal imino) -benzimidazol-l-yl) -methyl ] biphenyl-2carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 30 % of theoretical, Melting point: 219-221 °C C35H35N3O4 X H2O (579.69) Calculated: C 72.52 H 6.43 N 7.23 Found: 72.66 6.49 7.43 Example 24 3 4' - [ (2-n-Butyl-6- (3,4-dimethoxy-phthalimino) benzimidazol-l-yl) -methyl] biphenyl-2-carboxylic acid dihydrate Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(3,4-dimethoxy-phthalimino)benzimidazol-l-yl) -methyl ] biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 24.3 % of theoretical.
Melting point: 206-208 °C C35H31N3O6 x 2 H2O (625.68) Calculated: C 67.19 H 5.64 N 6.72 Found: 67.22 5.84 6.97 255 Example 244 41-[(2-n-Butyl-6-(N-(dimethylaminocarbonyl)-n-pentylamin o)-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid trifluoroacetate Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-(dimethylaminocarbonyl)n-pentylamino)-benzimidazol-l-yl)-methyl]biphenyl-2carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 81.8 % of theoretical, Melting point: 174-176 °C C33H40NAO3 X CF3COOH (654.73) Calculated: C 64.21 H 6.31 N 8.55 Found: 64.38 6.28 8.64 Example 245 4'-[ (2-n-Butyl-6-r(N-(4-phenylamino-n-butyl) -npentylamino)-benzimidazol-l-yl)-methyl]bipheny1-2carboxylicacid Prepared in analogous manner to Example 9 from tert.butyl 4'-((2-n-butyl-6-(N-(4-phenylamino-n-butyl)n-pentylamino)-benzImidazol-l-yl)-methyl]biphenyl-2carboxylate and trifluoroacetic acid in methylene chloride.
Example 246 4'-[(2-n-Butyl-6-cyclohexylaminocarbonylamino-benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared in analogous manner to Example 58 from 4'-[(6 amino-2-n-butyl-benzimidazol-l-yl)-methyl]-2-(1Htetrazol-5-yl)-biphenyl and cyclohexylisocyanate in methylene chloride.
Yield: 55.1 % of theoretical, 256 Melting point: 232-234 °C C32H36N8O (548.69) Calculated: C 70.05 Found: 69.86 H 6.61 6.66 N 20.42 20.25 Example 247 4' -[ (2-n-Butyl-6-dimethylaminoaminocarbonylaminobenz imidazol-l-yl) -methyl] -2-(lH-tetrazol-5-yl) -biphenyl Prepared in analogous manner to Example 58b from 4*-[(2n-butyl-6-dimethylaminoaminocarbonylamino-benz imidazoll-yl) -methyl] -2- (l-triphenylmethyl-tetrazol-5-yl) biphenyl and hydrochloric acid in ether/methanol/methylene chloride.
Yield: 69.8 % of theoretical, Melting point: 239-241°C C2eH30NaO (494.60) Calculated: C 67.99 H 6.11 N 22.65 Found: 67.85 6.08 22.55 Example 248 41 - [ (2-n-Butyl-6- (N-cyclohexylaminoaminocarbonylmethy lamino) -benzimidazol-l-yl) -methyl]-2-(lH-tetrazol5-yl)-biphenyl hydrate Prepared in analogous mariner to Example 58b from 4'-[(2n-butyl-6- (N-cyclohexylaminoaminocarbonylmethylamino) benzimidazol-l-yl) -methyl] -2- (1-triphenylmethyltetrazol-5-yl)-biphenyl and hydrochloric acid in methylene chloride/ether/methanol.
Yield: 97.5 % of theoretical, Melting point: 163-165OC C33H38N8OxH2O (580.73) Calculated: C 68.25 H 6.94 N 19.30 68.43 6.90 19.15 Found: 257 Example 249 ·-[ (2-n-Butyl-6-cyclohexylaminoaminocarbonylaminobenzimidazol-l-yl)-methyl]-2-trifluoromethanesulphonamino-biphenyl Prepared in analogous manner to Example 7 from 4*-[(6amino-2-n-buty1-benzimidazol-l-yl)-methyl]-2tri fluoromethanesulphonamino-biphenyl and cyclohexylisocyanate.
Yield: 90.9 % of theoretical, Melting point: 163-165°C C32H36N5O3S (627.73) Calculated: C 61.23 H 5.78 N 11.15 Found: 61.12 5.67 11.29 Example 250 4'-[(2-n-Butyl-6-cyclohexylaminocarbonyloxybenzimidazol-l-yl) -methyl ]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert. butyl 4' - [ ( 2-n-butyl-6-cyclohexylaminCcarbonyloxybenzimidazol-l-yl) -methyl ] biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 80.0 % of theoretical, Melting point: 218-219°C C32H3SN3O4 (525.65) Calculated: C 73.12 H 6 71 N 7.99 Found: 73.04 6.84 7.92 258 Example 251 4'-[(2-n-Butyl-6-cyclohexyloxycarbonylaminobenzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4’-[(2-n-butyl-6-cyclohexy loxycarbonylaminobenzimidazol-l-yl) -methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 90.9 % of theoretical, Melting point: 238-240 °C C32H35N3O4 (525.65) Calculated: C 73.12 H 6.71 N 7.99 Found: 73.18 6.74 8.11 Example 252 ·-( (2-n-Butyl-6-morpholinocarbonylamino-benzimidazol-lyl)-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4·-[(2-n-butyl-6-morpholinocarbonylaminobenzimidazol-l-yl) -methyl) biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 85.0 % of theoretical, Melting point: 278-279 °C C30H32N4°4 (512.61) Calculated: C 70.29 H 6.29 N 10.93 Found: 70-28 6-28 11-00 Example 253 4' - [ (2-n-Butyl-6-pyrrolidinocarbonylamino-benzimidazol1-yl)-methyl)biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4·-[(2-n-butyl-6-pyrrolidinocarbonylamino259 benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Example 254 4’-[(2-n-Butyl-6-(N-methylaminocarbonyl-N-(3-cyclohexyln-propyl) -amino) -benzimidazol-l-yl)-methyl]biphenyl-2carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-methylaminocarbonyl-N-(3cyclohexyl-n-propyl)-amino)-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 84.8 % of theoretical, Melting point: 215-216°C C36H„N4O3 (580.72) Calculated: C 74.45 H 7.64 N 9.65 Found: 74.52 7.75 9.76 Example 255 4' - [ (2-n-Butyl-6- (cis-hexahydrophthalimino-benzimidazol-l-yl )-methyl]-l-(lH-tetrazol-5-yl)-2-phenylnaphthalene Prepared in analogous manner to Example 59 from 4*-[(2n-butyl- (cis-hexahydrophthalimino-benz imidazol-l-yl) methyl]-l-cyano-2-phenyl-naphthalene and ammonium chloride/sodium azide. 260 Example 256 ’-((2-n-Propyl-6-(N-cyclohexylaminocarbonylmethylamino) -benz imidazol-l-yl) -methyl ] -1- (lH-tetrazol5-yl)-2-phenyl-naphthalene Prepared in analogous manner to Example 59 from 4’-[(2n-propyl-6- (N-cyclohexylaminocarbonyl-methyl-amino) benz imidazol-l-yl) -methyl ] -l-cyano-2-pheny1-naphthalene and ammonium chloride/sodium azide.
Example 257 4(2-n-Propyl-6-(N-cyclohexylaminocarbonyl-methylamino) -benzimidazol-l-yl) -methyl] -2 -phenyl-naphthalene1-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4 *-[(2-n-propyl-6-(N-cyclohexylaminocarbonylmethy lamino) -benzimidazol-l-yl) -methyl]-2-pheny1naphthalene-l-carboxylate and trifluoroacetic acid. Yield: 73.0 % of theoretical, Melting point: 193-195°C C36H38N<03 (574.70) Calculated: C 75.28 H 6.67 N 9.75 Found: 75.10 6.71 9.72 261 Example 258 4' — [(2-n-Butyl-6-(cis-hexahydrophthalimino) benzimidazol-l-yl)-methyl]-2-phenyl-naphthalene-lcarboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(cis-hexahydrophthalimino)benzimidazol-l-yl)-methyl]-2-phenyl-naphthalene-1carboxylate and trifluoroacetic acid.
Yield: 37.0 % of theoretical, Melting point: 215-218 °c C36H33N3O4 (571.65) Calculated: C 75 .63 H 5 -82 N 7 35 Found: 75 .47 5 .63 7 Jl 262 Example 259 4’-[(2-n-Butyl-6-(N-(n-dodecylaminocarbonyl) methylamino) -benzimidazol-l-yl) -methyl] biphenyl-2 carboxylic acid trifluoroacetate Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-(n-dodecylaminocarbonyl)methylamino) -benzimidazol-l-yl) -methyl)biphenyl-2carboxylate in trifluoroacetic acid/methylene chloride. Yield: 85.7 % of theoretical, Melting point: 61-62 °C C35H52N4O3 X CF3COOH (738.39) Calculated: C 66.65 H 7.23 N 7.58 Found: 66.68 7.47 7.83 Example 2 60 * - [ (2-n-Butyl-6- (N- (cyclohexylaminocarbonyl) -n-octylami no)-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 72 from ethyl 4 · - [ (2-n-butyl-6- (N- (cyclohexylamino-carbonyl) -noctylamino) -benzimidazol-l-yl) -methyl )bi-phenyl-2carboxylate in ethanol/2N sodium hydroxide solution. Yield: 94.9 % of theoretical, Melting point: 151-152°C c*oH52N403 (636.88) Calculated: C 75.44 H 8.23 N 8.80 Found: 75.63 8.37 8.92 263 Example 261 ’ - [ (2-n-Buty 1-6-(N-(n-octylaminocarbonyl) -methylamino) -benzimidazol-l-yl) -methyl ] biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert. butyl 4' - [ (2-n-buty 1-6- (N- (n-octylaminocarbonyl) 10 methylamino) -benzimidazol-l-yl) -methyl ]biphenyl-2carboxylate in trifluoroacetic acid/methylene chloride. Yield: 87.5 % of theoretical, Melting point: 169-170°C C35H„N4O3 (568.76) Calculated: C 73.91 H 7.80 N 9.85 Found: 73.98 7.95 9.78 Example 262 4·-[ (2-n-Butyl-6-(cis-hexahydrophthalimino)benzimidazol-l-yl) -methyl]-2-(lH-tetrazol-5-yl) -biphenyl Prepared in analogous manner to Example 58 from 4*-[(2n-butyl-6- (cis-hexahydrophthalimino) -benzimid-azol-125 yl) -methyl]-2-(l-tripheny lmethyl-tetrazol-5-yl) -biphenyl and hydrochloric acid in ether/methanol/methylene chloride.
Yield: 47.6 % of theoretical.
Melting point: 147-149°C C33H33N7O2 (559.67) Calculated: C 70.82 H 5.94 N 17.52 Found: 70.61 6.12 17.63 264 Example 263 4'-[(2-n-Butyl-6-(endo-bicyclo[2.2.2]oct-5-ene-2,3dicarboxylic acid-imino) -benzimidazol-l-yl) -methyl]biphenyl-2-carboxylic acid trifluoroacetate Prepared in analogous manner to Example 9 from tert.butyl 4 · -[ (2-n-butyl-6- (endo-bicyclo[2.2.2] oct-5ene-2,3-dicarboxylic acid-imino) -benzimidazol-l-yl) methyl ]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 88.6 % of theoretical, Melting point: 161-163°C C35H33N3O4 X CF3COOH (673.69) Calculated: C 65.96 H 5.08 N 6.23 Found: 65.72 4.99 6.11 Example 264 41 -( (2-n-Butyl-6- (methyl-5-norbornene-2,3-dicarboxylic acid-imino)-benzimidazol-l-yl)-methyl ]biphenyl-2carboxylic acid (isomer mixture) Prepared in analogous manner to Example 9 from tert.butyl 4’-[(2-n-butyl-6- (methyl-5-norbornene-2,3dicarboxyl ic acid-imino) -benzimidazol-l-yl) -methyl ] bi phenyl-2-carboxylate (isomer mixture) and trifluoroacetic acid in methylene chloride. 265 Example 265 4(2-n-Buty1-6-(trans-hexahydrophthalimino) -benzimidaz ol-l-yl)-methyl]biphenyl-2-carboxylic acid dihydrate Prepared in analogous manner to Example 9 from tert.butyl 4' -[(2-n-butyl-6-(trans-hexahydrophthalimino) -benzimidazol-l-yl) -methyl] biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 60.7% of theoretical, Melting point: 188-190°C C33H33N3O4 X 2 HZO (571.67) Calculated: C 69.33 H 6.52 N 7.35 Found: 69.48 6.40 7.57 Example 266 ' -[ (2-n-Butyl-6- (3,6-endoxo-l, 2,3,6-tetrahydrophthalimi no) -benzimidazol-l-yl) -methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(3,6-endoxo-l,2,3,6-tetrahydrophthalimino) -benzimidazol-l-yl) -methyl ] biphenyl-2carboxylate and trifluoroacetic acid in methylene chloride. 266 Example 267 * — [ (2-n-Butyl-6-(cis-5-norbornene-endo-2,3-dicarboxylic acid-imino)-benzimidazol-l-yl)-methyl]biphenyl-2carboxylic acid monohydrate Prepared in analogous manner to Example 9 from tert.butyl 4’-((2-n-butyl-6-(cis-5-norbornene-endo-2,3* dicarboxylic acid-imino) -benzimidazol-l-yl) -methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 22.1% of theoretical, Melting point: 263-265°C C3«H31N3Oa X H20 (563.65) Calculated: C 72.44 H 5.90 N 7.45 Found: 72.28 5.81 7.46 Example 268 ’ — [ (2-n-Butyl-6- (2-carboxy-cyclohexy lcarbony lamino) benzimidazol-l-yl) -methyl]biphenyl-2-carboxylic acid 0.6 g (1.5 mmol) of 41-[ (6-amino-2-n-buty 1-benzimidazoll-yl)-methyl J biphenyl-2-carboxylic acid are dissolved in 150 ml of methylene chloride With heating and cooled to ambient temperature. After the addition of 240 mg (1.55 mmol) of cis-cyclohexan-l,2-dicarboxylic acid anhydride the mixture is stirred for 5 hours at ambient temperature. The reaction product which crystallises out is suction filtered, washed with methylene chloride and dried in a vacuum drying chamber at 50*C.
Yield: 0.58 g (69.8% of theory), Melting point: 186-188*c C33H35N3O5 (553.66) Calculated: C 71.59 H 6.37 N 7.59 Found: 71.42 6.56 7.56 267 Example 269 ’ — [ (2-n-Butyl-6-(3-carboxy-cis-5-norbornene-endo-25 carbonylamino)-benzimidazol-l-yl)-methyl]biphenyl-2carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4 ’ —[(2-n-butyl-6-(cis-5-norbornene-endo-2,310 dicarboxylic acid imino)-benzimidazol-l-yl)methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 17.1% of theory, Melting point: 199-201’C C34H33N3O5 (563.66) Calculated: C 72.44 H 5.90 N 7.45 Found: 72.26 5.82 7.44 268 Example 270 ’-[(2-n-Butyl-6-dimethylaminocarbonyloxy-benzimidazoll-yl) -methyl)biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-dimethylaminocarbonyloxybenzimidazol-l-yl) -methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 81.9% of theory, Melting point: 241-242*C C28HZ3N3O4 (471.56) Calculated: C 71.32 H 6.20 N 8.91 Found: 71.15 6.28 8.89 Example 271 4'-((2-n-Butyl-6-(N-acetyl-n-octylamino) -benzimidazol-lyl) -methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-acetyl-n-octylamino)benzimidazol-l-yl,-methyl]biphenyl-2-carboxylate . Yield: 77.2% of theory, Melting point: 192-193C C35H„N3O3 (553.74) Calculated: C 75.92 H 7.83 N 7.59 Found: 75.75 8.03 7.45 Example 272 Tert.-butyl 4' - [ (2-n-butyl-6-(2-phenylethylaminocarbonyl) -benzimidazol-l-yl)-methyl]biphenyl-2carboxylate 484 mg (1 mmol) of tert.-butyl 4*-((2-n-butyl-6-carboxybenzimidazol-1-yl) -methyl]biphenyl-2-carboxylate are 269 dissolved in 10 ml of absolute tetrahydrofuran and cooled to -20 *C with stirring and cooling with dry ice/isopropanol. At this temperature 101 mg (1 mmol) of N-methylmorpholine are added. The resulting mixture is then cooled to -30 "C and a solution of 136 mg (1 mmol) of isobutylchloroformate dissolved in 5 ml of absolute tetrahydrofuran is slowly added dropwise. To complete the formation of the mixed anhydride the mixture is stirred for a further hour at -40*C. At -40*C 134 mg (1.1 mmol) of 2-phenylethylamine dissolved in 2 ml of absolute tetrahydrofuran are slowly added dropwise.
Then the mixture is allowed to rise slowly to ambient temperature and stirred for 16 hours at ambient temperature. The solvent is distilled off, the remaining viscous oil is taken up in saturated common I b salt solution/ethyl acetate and extracted 3 times in all with ethyl acetate. The ethyl acetate phases are dried over sodium sulphate and evaporated down. The viscous oil is dissolved in methylene chloride and purified over a silica gel column (eluant: methylene chloride/ethanol 50:1 and 25:1).
Yield: 505 mg (86% of theory), oil, Rf value: 0.5 (silica gel: ethanol/methylene chloride - 1:19) C38H41N3O3 (587.80) Calculated: C 77.65 Η 7.03 N 7.15 Found: 77.58 7.24 7.34 The following compounds are obtained analogously: tert.butyl 4' - [(2-n-butyl-6-(2-phenylaminoethylaminocarbony1)-benzimidazol-l-yl)-methyl]biphenyl2-carboxylate oil, Rc value: 0.45 (silica gel: ethanol/methylene - chloride = 1:19, tert.butyl 4'-[(2-n-butyl-6-(5-carboxy-n270 pentylaminocarbonyl)-benzimidazol-l-yl)-methyl)biphenyl2-carboxylate Melting point: 166-167"C Example 273 4'-[(2-n-butyl-6-(2-phenylethylaminocarbonyl)benzimidazol-l-yl) -methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4’-[(2-n-butyl-6-(2-phenylethylaminocarbonyl) -benzimidazol-l-yl)-methyl]biphenyl-2carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 19.7% of theory> Melting point: 208-210’C C3AH33N3O3 (531.65) Calculated: C 76.81 H 6.26 N 7.90 Found: 76.69 6.48 7.92 Example 274 4(2-n-Butyl-6-(2-phenylaminoethylamiriocarbonyljbenzimidazol-l-yl)-methyl] bipheny 1-2-carboxylic acid x 1.5 HC1 Prepared analogously to Example 9 from tert.butyl 4'[(2-n-buty1-6-(2-phenylaminoethylaminocarbonyl)benzimidazol-l-yl) -methyl] bipheny 1-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 30% of theory, Melting point: 240-242*C C36H34NaO3 X 1.5 HC1 (601.36) Calculated: C 67.91 H 5.95 N 9.32 Found: 67.88 5.93 9.15 271 Example 275 4·-[(2-n-Butyl-6-(5-carboxy-n-pentylaminocarbonyl)benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 41-[(2-n-butyl-6-(5-carboxy-n-pentylamino carbonyl) -benzimidazol-l-yl) -methyl ] biphenyl-2carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 37.4% of theory.
Melting point: from 116*C (decomp.) C37H35N3O5 (541.70) Calculated: C 70.96 H 6.51 N 7.76 Found: 70.84 6.42 7.85 Example 276 4(2-n-Butyl-6-(2-carboxy-propionyl)-benzimidazol-l yl)-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 72 from methyl 4 · - [(2-n-butyl-6-(2-carboxy-propionyl)-benzimidazol-lyl) -methyl Jbipheny 1-2 -carboxylate and sodium hydroxide solution/methanol. 272 Example 277 Tert. butyl 4 ’ - [(2-n-butyl-6-homophthaliminobenzimidazol-l-yl) -methyl ] -biphenyl-2-carboxylate 1.5 g (3.3 mmol) of tert.butyl 4'-[ (6-amino-2-n-butylbenzimidazol-l-yl) -methyl ]biphenyl-2-carboxylate and 0.6 g (3.63 mmol) of homophthalic acid anhydride are refluxed for 20 hours in 20 ml of pyridine. Then the solvent is removed in vacuo and the residue is purified over a silica gel column (particle size 0.063-0.2 mm; eluant: methylene chloride/ethanol = 100:2, 100:3 and 100:5).
Yield: 15.2% of theory.
Melting point:109-112’C C38H37N3O4 (599.73) Calculated: C 76.10 H 6.22 N 7.01 Found: 75.90 6.28 6.90 The following compounds are obtained analogously: tert. butyl 4 · - [ (2-n-butyl-6- (3,3-tetramethyleneglutar imino) -benzimidazol-l-yl) -methyl]biphenyl-2carboxylate tert. butyl 4' - [ ( 2-n-butyl-6- ( 3,3-pentamethyleneglutarimino) -benzimidazol-l-yl) -methyl ]biphenyl-2carboxylate tert. butyl 4 · - ( (2-n-butyl-6- (7-methoxy-homophthalimino) benz imidazol-l-yl) -methyl ] biphenyl-2-carboxylate tert.butyl 4' -[ (2-n-butyl-6- (4,4-dimethyl-7-methoxyhomophthalimino) -benzimidazol-l-yl) -methyl] biphenyl-2carboxylate tert.butyl 4·-[(2-n-butyl-6-(6,7-dimethoxy273 homophthalimino)-benzimidazol-l-yl)-methyl]biphenyl-2carboxylate tert.butyl 4'-[(2-n-butyl-6-(6,7-dimethoxy-4,4-dimethylhomophthalimino) -benzimidazol-l-yl) -methyl] biphenyl-2carboxylate tert.butyl 4· -[ (2-n-butyl-6-glutarimino-benzimidazol-lyl)-methyl]biphenyl-2-carboxylate tert.butyl 4’-[(2-n-butyl-6-(3-methy1-glutarimino)benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate tert.butyl 4'-[(2-n-butyl-6-(3,3-dimethyl-glutarimino)benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate tert.butyl 4'-[(2-n-butyl-6-(3-ethyl-3-methylglutarimino)-benzimidazol-l-yl) -methyl]biphenyl-2carboxylate 4' - [ (2-n-butyl-6-(cis-hexahydrophthal imino) benzimidazol-l-yl)-methyl]-2-(l-triphenylmethyltetrazol-5-yl) biphenyl tert.butyl 4’-[(2-n-butyl-6-(4,4-dimethylhomophthal imino) -benzimidazol-l-yl) -methyl] -biphenyl-2carboxylate tert.butyl 4’-[(2-n-butyl-6-(5-methylhexahydrophthal imino) -benzimidazol-l-yl) methyl]biphenyl-2-carboxylate Oil, Rf value: 0.75 (silica gel; ethyl acetate/petroleum ether = 4:1) 274 Example 278 ' - [ (2-n-Butyl-6-homophthalimino-benzimidazol-l-yl)5 methyl)biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4' - [ (2-n-buty1-6-homophthaliminobenzimidazol-l-yl) -methyl ] biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 79 % of theory, Melting point: 171 -17TC C 3^12? 3° 4 <543’62> Calculated: C 75.12 H 5.38 N 7.73 Found: 74.95 5.18 7.64 Example 279 20 4·-[(2-n-Butyl-6-(4,4-dimethyl-homophthalimino)benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4(2-n-butyl-6-(4,4-dimethyl25 homophthalimino) -benzimidazol-l-yl) -methyl) biphenyl-2carboxylate and trifluoroacetic acid in methylene chloride.
Yield:77.4% of theory, Melting point: 299-301’C 30 c3^3^3O4 * HjO (589.89) Calculated: C 73.33 H 5.98 N 7.13 Found: 73.60 6.14 7.33 275 Example 280 — [ (2-n-Buty 1-6- (3,3-tetramethylene-glutarimino) 5 benzimidazol-l-yl) -methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4(2-n-butyl-6-(3,3-tetramethyleneglutarimino) -benzimidazol-l-yl)-methyl]biphenyl-210 carboxylate and trifluoroacetic acid in methylene chloride.
Yield:40.0% of theory.
Melting point: 191-194"C C34H35N3Oa (549.64) Calculated: C 74.29 H 6.42 N 7.65 Found: 74.08 6.31 7.52 Example 281 4’-[(2-n-Butyl-6-(3,3-pentamethylene-gluarimino)benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from 25 tert.butyl 4'-[(2-n-butyl-6-(3,3-entamethyleneglutarimino) -benzimidazol-l-yl) -methyl ]biphenyl-2carboxylate and trifluoroacetic acid in methylene chloride.
Yield:31.0% of theory, 30 Melting point: 182-185’C C35H37N3O4 (563.67) Calculated: C 74.57 H 6.62 N 7.46 Found: 74.43 6.52 7.32 276 Example 232 4' - [(2-n-Butyl-6-(7-methoxy-homophthalimino) benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4 *-[ (2-n-butyl-6-(7-methoxy-homophthalimino) benzimidazol-l-yl) -methyl] biphenyl-2-carboxylate and trifluoroacetic acid.
Example 283 4·-[(2-n-Butyl-6-(4,4-dimethyl-7-methoxyhomophthal imino) -benzimidazol-l-yl) -methyl )biphenyl-2carboxylic acid Prepared in analogous manner to Example 9 from tert. butyl 41 - ((2-n-buty 1-6- (4,4-dimethy1-7 -methoxyhomophthal imino) -benzimidazol-l-yl) -methyl] biphenyl-2 carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 60.R of theory, Melting point:104 -105"C C37H35N3O5 (601.70) Calculated: C 73.86 H 5.86 N 6.98 Found: 73.92 6.04 7.11 Example 284 4· — [(2-n-Butyl-6-(6,7-dimethoxy-homophthalimino) benzimidazol-l-yl)-methyl)biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4’-[(2-n-butyl-6-(6,7-dimethoxy277 homophthalimino) -benzimidazol-l-yl) -methyl ] biphenyl-2carboxylate and trifluoroacetic acid in methylene chloride.
Example 285 · - [ (2-n-Butyl-6- (6,7-dimethoxy-4,4-dimethylhomophthal imino) -benzimidazol-l-yl) -methyl]biphenyl-2carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4’-[(2-n-butyl-6-(6,7-dimethoxy-4,4-dimethylhomophthal imino) -benz imidazol-l-yl) -methyl ] biphenyl-2carboxylate and trifluoroacetic acid in methylene chloride.
Example 286 ' - [ (2-n-Butyl-6-(3,3-pentamethylene-glutarimino)benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared in analogous manner to Example 59 from 4*-[(2n-butyl-6- (3,3-pentamethylene-giutarimino) -benzimidazoll-yl) -methyl]-2-cyano-biphenyl and sodium azide/ammonium chloride.
Yield:29.0% of theory, Melting point: from 140°C (sintering) C35H37N7O2 (587.70) Calculated: C 71.52 H 6.35 N 16.68 Found: 71.37 6.20 16.71 278 Example 287 · — [(2-n-Butyl-6-(3,3-tetramethylene-glutarimino)benz imidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared in analogous manner to Example 59 from 4*-[(2n-butyl-6-(3,3-tetramethylene-glutarimino)-benzimidazoll-yl) -methyl )-2-cyano-biphenyl and sodium azide/ammonium chloride.
Yield:31.0% of theory, Melting point: from 166°C (sintering) C3«H35N7O2 (573.68) Calculated: C 71.18 H 6.15 N 17.09 Found: 71.10 6.22 17.20 Example 288 ’-[(2-n-Butyl-6-glutarimino-benzimidazol-l-yl)methyl]bisphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4*-[ (2-n-butyl-6-glutarimino-benzimidazol-lyl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield:82.0% of theory, Melting point: > 220 *c C3qH29N3O4 (495.56) Calculated: C 72.71 H 5.90 N 8.48 Found: 72.56 5.79 8.22 279 Example 289 · — [ (2-n-Butyl-6-glutarimino-benzimidazol-l-yl) -methyl]2-(lH-tetrazol-5-yl)-biphenyl Prepared in analogous manner to Example 59 from 4*-[(2n-butyl-6-glutarimino-benzimidazol-l-yl) -methyl ] -2cyano-biphenyl and sodium azide/ammonium chloride. Yield:47.0% of theory, Melting point: from 139°C (sintering) C30H2eN7O2 (519.59) Calculated: C 69.34 H 5.62 N 18.87 Found: 69.30 5.52 18.69 Example 290 4'-[ (2-n-Butyl-6-(3-methyl-glutarimino) -benzimidazol-lyl )-methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert. butyl 4' - [ (2-n-butyl-6- (3-methyl-glutarimino) benzimidazol-l-yl) -methyl ]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride. Yield:39.0% of theory, Melting point: > 220°C C31H31N3O4 (509.58) Calculated: C 73.06 H 6.13 N 8.25 Found: 72 .91 5 .88 8 .02 Example 291 ’ -[ (2-n-Butyl-6- (3-methyl-glutarimino) -benzimidazol-lyl )-methyl] -2-. (lH-tetrazol-5-yl)-biphenyl Prepared in analogous manner to Example 59 from 4'-[(2n-butyl-6-( 3-methyl-glutarimino) -benzimidazol-l-yl)methyl]-2-cyano-biphenyl and sodium azide/ammonium 280 chloride.
Yield: 28.0% of theory, Melting point: from 157°C (sintering) GsjHajNyOj (533.61) Calculated: C 69.77 H 5.86 N 18.38 Found: 69.69 5. 81 18. 16 Example 292 * - [ (2-n-Butyl-6- (3,3-dimethyl-glutarimino) benzimidazol-l-yl) -methyl ] biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4 ' -[ (2-n-butyl-6- (3,3-dimethyl-glutarimino) benzimidazol-l-yl) -methyl ] biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 41.0% of theory, Melting point: > 220 *c CaaHaaNsO* (523.61) Calculated: C 73.40 H 6.35 N 8.03 Found: 73. 29 6. 21 7. 91 281 Example 293 · - [(2-n-Butyl-6-(3,3-dimethyl-glutarimino)benzimidazol-l-yl) -methyl]-2-(lH-tetrazol-5-yl) -biphenyl Prepared in analogous manner to Example 59 from 4’-((2n-butyl-6- (3,3-dimethyl-glutarimino) -benzimidazol-l-yl) methyl ]-2-cyano-biphenyl and sodium az ide/ammonium chloride.
Yield:29.0% of theory.
Melting point:from 151"C (sintering) C32H33N7O2 (547.64) Calculated: C 70.18 H 6.07 N 17.91 Found: 69.91 5.98 17.85 Example 294 ·-[ (2-n-Buty 1-6- (3-ethyl-3-methyl-glutarimino, benzimidazol-l-yl) -methyl]biphenyl-2-carboxylic acid Prepared in analogous manner to Example 9 from tert.butyl 4' - ((2-n-butyl-6-(3-ethyl-3-methylglutar imino) -benzimidazol-l-yl) -methyl ]biphenyl-2carboxylate and trifluoroacetic acid in methylene chloride.
Yield:38.0% of theory, Melting point: > 220 *c C33H35N3O4 (537.63) Calculated: C 73.72 H 6.56 N 7.82 Found: 73.55 6.41 7.76 282 4' — [ (2-n-Butyl-6-(3-ethyl-3-methyl-glutarimino) benzimidazol-l-yl) -methyl]-2-(lH-tetrazol-5-yl) -biphenyl Example, 295 Prepared in analogous manner to Example 59 from 4’-[(2n-butyl-6- (3-ethyl-3-methyl-glutarimino) -benzimidazol-lyl)-methyl ]-2-cyano-biphenyl and sodium azide/ammonium chloride.
Yield:26.0% of theory.
Melting point:from 138’C (sintering) C33H35N7O2 (561.67) Calculated: C 70.56 H 6.28 N 17.46 Found: 70.47 6-Q2 17-33 Example 296 4'-[(2-n-Butyl-5-(N-cyclohexylaminocarbonylmethylamino) -benzimidazol-l-yl) -methyl] -2- (1H-tetrazol5-yl biphenyl Prepared analogously to Example 58b from 4'-[ (2-n-butyl5- (N-cyclohexylaminocarbonyl-methylamino) -benzimidazoll-yl) -methyl]-2-(l-triphenylmethyl-tetrazol-5-yl)biphenyl and hydrochloric acid in methylene chloride/ether/methanol.
Yield: 76.2% of theory, Melting point: 150-152eC C33H38N8O (562.72) Calculated: C 70.44 H 6.80 N 19.91 Found: 70.32 7.05 19.76 283 Example 297 4'-[(2-n-Butyl-6-(5-methyl-hexahydrophthalimino)benzimidazol-l-yl)biphenyl-2-carboxylic acid Prepared analogously to Example 9 from tert.butyl 4'[(2-n-butyl-6-(5-methyl-hexahydrophthalimino)benzimidazol-l-yl) -methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 37% of theory, Melting point: 143-146"C C34H35N304 (549.67) Calculated: C 74.29 H 6.42 N 7.62 Found: 74.47 6.67 7.55 Example 298 ’ -[(2-n-Butyl-5-(cis-hexahydrophthalimino)benzimidazol-l-yl)-methyl]-2-(lH-tetrazol-5-yl)-biphenyl Prepared analogously to Example 58 from 4' - [ (2-n-butyl5- (cis-hexahydrophthalimino) -benzimidazol-l-yl) -methyl] 2-(l-triphenylmethyl-tetrazpl-5-yl)-biphenyl and hydrochloric acid/ethanol Yield: 59.5% of theory, Melting point: 230-232’C C33H33N7O2 (559.67) Calculated: C 70.82 H 5.94 N 17.52 Found: 70.64 6,10 17.72 Each suitable compound of the formula I, for example the compounds of the above examples, may be used as active substance in the following examples of pharmaceutical preparations: 284 Example I Ampoules containing 50 mg of active ingredient per 5 ml Active ingredient KH2POa Na2HPO4 X 2HZO NaCl Water for injections ad mg 2 mg mg 12 mg ml Preparation: The buffer substances and the isotonic agent are dissolved in part of the water. The active ingredient is added and after it is completely dissolved, the solution is made up to the nominal volume with water.
Example II Ampoules containing 100 mg of active ingredient per 5 ml Active ingredient 100 mg Methylglucamine 35 mg Glycofurol 1,000 mg Polyethylene glycol-polypropylene glycol block polymer 250 mg Water for injections ad 5 ml Preparation: Methylglucamine is dissolved in part of the water and the active ingredient is dissolved with stirring and heating. After adding the solvent, the solution is made up to the nominal volume with water. 285 Example III Tablets containing 50 mg of active ingredient Active ingredient 50.0 mg Calcium phosphate 70.0 mg Lactose 40.0 mg Corn starch 35.0 mg Polyvinylpyrrolidone 3.5 mg Magnesium stearate 1.5 mg 200.0 mg Preparation: The active ingredient, CaHPO*, lactose and corn starch are moistened evenly with an aqueous PVP solution. The mixture is passed through a 2 mm sieve, dried at 50 °C in an oven with circulating air and sieved again.
After admixing the lubricant, the granules are pressed on a tableting machine. 2g Example IV Coated tablets containing 50 mg of active ingredient Active ingredient 50.0 mg Lysine 25.0 mg Lactose 60.0 mg Corn starch 34.0 mg Gelatine 10.0 mg Magnesium stearate 1.0 mg 180.0 mg 286 Preparation: The active ingredient is mixed with the auxiliaries and moistened with an aqueous gelatine solution. After sieving and drying, the granules are mixed with magnesium stearate and pressed to form cores.
The cores thus prepared are coated with a shell in accordance with known processes. Dyestuff may be added to the coating suspension or solution.
Example V Coated tablets containing 100 mg of active ingredient Active ingredient 100.0 mg Lysine 50.0 mg Lactose 86.0 mg Corn starch 50.0 mg Polyvinylpyrrolidone 2.8 mg Microcrystalline celluse 60.0 mg Magnesium stearate 1.2 mg 350.0 mg Preparation: The active ingredient is mixed with the auxiliaries and moistened with an aqueous PVP solution. The moist mixture is passed through a 1.5 mm sieve and dried at 45 °C. After drying, the mixture is sieved again and the magnesium stearate is admixed. This mixture is pressed to form cores.
The cores thus prepared are coated with a shell in 287 accordance with known processes. Dyestuffs may be added to the coating suspension or solution.
Example VI Capsules containing 250 mg of active ingredient Active ingredient 250.0 mg IQ Corn starch 68.5 mg Magnesium stearate 1.5 mg 320.0 mg Preparation: Active ingredient and corn starch are mixed and moistened with water. The moist mixture is sieved and dried. The dry granules are sieved and mixed with magnesium stearate. The final mixture is placed in size 1 hard gelatine capsules.
Example VII 2£ Oral suspension containing 50 mg of active ingredient per 5 ml Active ingredient 50.0 mg Hydroxyethylcellulose 50.0 mg Sorbic acid 5.0 mg Sorbitol 70 % strength 600.0 mg Glycerol 200.0 mg Flavour 15.0 mg Water ad 5.0 ml Preparation: 288 Distilled water is heated to 70 °C. Hydroxyethylcellulose is dissolved in the water with stirring. The solution is cooled to ambient temperature by adding sorbitol solution and glycerol. Sorbic acid, flavour and active g ingredient are added at ambient temperature. Air is removed from the suspension by evacuating while stirring. 5.0 ml contains one dose = 50 mg.
Example VIII Suppositories containing 100 mg of active ingredient Active ingredient 100.0 mg Solid lard 1,600.0 mg 1,700.0 mg 20 Preparation: The hard fat is melted. The ground active substance is dispersed homogeneously in the melt at 40 °C. The mixture is cooled to 38 °C and poured into slightly pre-cooled suppository moulds.

Claims (15)

1. CLAIMS in which R t denotes a hydrogen, fluorine, chlorine or bromine atom, an alkyl group having 1 to 4 carbon atoms, which may be substituted by a hydroxy, alkoxy, amino, alkylamino, dialkylamino or acylamino group, an alkoxy group having 1 to 4 carbon atoms, which may be substituted in the 2, 3 or 4 position by a hydroxy, alkoxy, amino, alkylamino, dialkylamino or imidazolyl group, a hydroxy, phenylalkoxy, acyloxy, trifluoromethylsulphonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, cycloalkylaminocarbonyloxy, cycloalkylalkylaminocarbonyloxy, arylaminocarbonyloxy, aralkylaminocarbonyloxy, alkoxycarbonyloxy, cycloalkoxycarbonyloxy, cycloalkylalkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, trifluoromethyl, cyano, nitro, alkylmercapto, alkylsulphinyl, alkylsulphonyl, aminosulphonyl, 290 alkylaminosulphonyl, dialkylaminosulphonyl, arylaminosulphonyl, acylaminosulphonyl or acyl group, an amino group, which may be monosubstituted by an 5 imidazolylalkyl, dialkylaminoalkanoyl, acyl, cycloalkoxycarbonyl, cycloalkylalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl or trifluoroacetyl group, by a bicyclic or tricyclic alkyl group having 7 to ll carbon atoms, by an alkylsulphonyl group having 1 10 to 4 carbon atoms, by an alkoxycarbonyl group having a total of 2 to 7 carbon atoms or by a thiazolidin-3-ylcarbonyl group substituted by an alkoxycarbonyl group, an alkylamino group having 1 to 6 carbon atoms, which 15 may be substituted at the nitrogen atom by an alkyl, alkylsulphonyl or acyl group, wherein, if the acyl group is an alkanoyl group, it may be additionally substituted by an alkoxy group, and the alkyl substituent may be substituted at position 2 by a 20 hydroxy, alkoxy or arylamino group, an amino group monosubstituted or disubstituted by a cycloalkyl, cycloalkylalkyl, phenylalkyl or phenyl group, wherein the substituents may be the same or 25 different, an N-alkyl-cycloalkylamino, N-alkylcycloalkylalkyl-amino, N-alkyl-phenylalkylamino or Nalkyl-phenylamino group, a pyrrolidino, piperidino or hexamethyleneimino group 30 optionally substituted by an alkyl, cycloalkyl or phenyl group, an N-alkoxycarbonyl-alkylamino, N-cycloalkoxycarbonylalkylamino, N-cycloalkylalkoxycarbonyl-alkylamino, ,N35 aryloxycarbonyl-alkylamino or N-aralkoxycarbonylalkylamino group, in which the alkyl group may contain 1 to 6 carbon atoms in each case, an alkoxycarbonylamino, cycloalkoxycarbonylamino, cycloalkylalkoxycarbonylamino, 291 aryloxycarbonylamino, aralkoxycarbonylamino, acylamino or alkylsulphonylamino group substituted at the nitrogen atom by a cycloalkyl, cycloalkylalkyl or aralkyl group, a carbonyl group which is substituted by an alkyl group substituted in the 2 or 3 position by a hydroxy, alkanoyloxy or alkylamino group, by a hydroxycarbonylalkyl, hydroxy, alkoxy, amino, cycloalkyl amino, cycloalkylalkylamino, arylamino or aralkylamino group, by an alkylamino group substituted in the 2 or 3 position by an arylamino group, or by an alkylamino group having 1 to 5 carbon atoms optionally substituted in the alkyl moiety by a carboxy group, which maybe substituted in each case additionally at the nitrogen atom by an alkyl group. an aminoacetylamino group optionally substituted by an alkoxycarbonyl group having a total of 2 to 5 carbon atoms, an aminocarbonylamino or aminothiocarbonylamino group, which may be monosubstituted, disubstituted or trisubstituted by an alkyl group having 1 to 20 carbon atoms, by an alkenyl or alkynyl group having 3 to 5 carbon atoms in each case, by a bicyclic or tricyclic alkyl group having 7 to 11 carbon atoms, by a cycloalkyl, cycloalkylalkyl, aralkyl or aryl group, wherein the substituents may be the same or different, and a methylene group in a cycloalkyl radical having 5 to 7 carbon atoms may be replaced by an oxygen atom, and an alkyl group may be substituted in the 4, 5 or 6 position by a hydroxy, alkanoyl or trifluoroacetyl group, a cycloalkyleneiminocarbonylamino group having 4 to 6 carbon atoms in the cycloalkyleneimino moiety or a morphol inocarbonylamino group, which may both be substituted at the amino nitrogen by an alkyl group 292 having 1 to 20 carbon atoms, or by a cycloalkyl, cycloalkylalkyl, aralkyl or aryl group, a phthalimino, homophthalimino, 2-carboxypheny1carbonyl amino, 2-carboxyphenylmethy1amino, 2-carboxyphenylmethylenecarbonylamino, or 2-carboxymethylenephenylcarbonyl amino group, wherein a carbonyl group in a phthalimino group may be replaced by a methylene group, and a methylene group in a homopthalimino, 2-carboxypheny lmethylenecarbonyl amino or 2-carboxymethylenephenyl carbonylamino group may be substituted by one or two alkyl groups, and additionally the above phenyl nuclei may be mono or disubstituted by alkyl or alkoxy groups, whilst the substituents may be the same or different, and may at the same time be completely or partially hydrogenated, a bicycloalkane-3-carboxylic acid amino or bicycloalkane-3-carboxylic acid amino group, a bicycloalkane-2,3-dicarboxylic acid imino or bicycloalkane-2,3,-dicarboxylic acid imino group substituted in the 2 position by a carboxy group, wherein the bicycloalkane and bicycloalkene moiety each contain 9 or 10 carbon atoms, may be substituted by 1, 2 or 3 methyl groups, and an endomethylene group may be replaced by an oxygen atom, a glutaric acid imino or 3carboxy-n-propylenecarbony! group, in which the npropylene group maybe perfluorinated in each case, may be substituted by one or two alkyl groups or by a tetramethylene or pentamethylene group, or a 5,7-dioxa-lH,3H-imidazo[1,5-c]thiazolyl group, R 2 denotes the meanings for R x mentioned above, a 2imidazolidon-l-yl or 3,4,5,6-tetrahydro-2-pyrimidon-l-yl group optionally substituted in the 3 position by an alkyl, cycloalkyl, cycloalkylalkyl or aralkyl group, or a tetrazolyl group or R x and R 2 together with 2 carbon atoms of the 293 neighbouring phenyl ring denote a phenyl or l-alkyl-3,3dialkyl-2,3-dihydropyrrol-2-one group, R 3 denotes a hydrogen, fluorine, chlorine or bromine 5 atom, an alkyl group having 1 to 6 carbon atoms, in which a methylene group may be replaced by an oxygen or sulphur atom, a sulphinyl, sulphonyl or alkylamino group, and a IQ methyl group may be substituted by a hydroxy, alkoxy, amino, alkylamino or dialkylamino group, but wherein the methylene group next to the benzimidazole ring may not be replaced by a sulphinyl or sulphonyl group, and when a methylene group is replaced and a methyl group is 15 substituted at the same time, they must be separated from one another by at least 2 carbon atoms, an alkenyl or alkynyl group each having 3 to 5 carbon atoms, a phenylalkyl group, a cycloalkyl or cycloalkylalkyl group, in which the cycloalkyl moiety may contain 5 to 7 carbon atoms in 25 each case, an aryl, hydroxy or imidazolylalkylamino group, an alkylamino group having 1 to 4 carbon atoms, an aminocarbonyl group, which may be substituted by an alkyl or cycloalkyl group having 5 to 7 carbon atoms, a 5-membered heteroaromatic ring, which contains an NH group, an oxygen or sulphur atom, wherein this 535 membered heteroaromatic ring mentioned above may additionally contain a further 1 to 3 N atoms, or a 6membered heteroaromatic ring, which may contain 1 or 2 294 nitrogen atoms, wherein the 5-membered and 6-membered heteroaromatic rings mentioned above may be substituted by one or, with the exception of the tetrazolyl group, by two alkyl groups, R 4 denotes an amino, phthalimino, aminomethyl, cyano, tert.-butoxycarbonyl or 1-(triphenylmethyl)-tetrazolyl group, these compounds being intermediate products, a group containing a BrBnsted acid or a radical which can be converted in vivo to a group containing a BrBnsted acid, these compounds being angiotension-11-antagonists. R s and R 6 each denote a hydrogen atom or R 5 and R 6 together with the two ortho position carbon atoms denote a phenyl group, wherein, provided that nothing else has been mentioned, the acyl group mentioned in the definition of the radicals R x to R^ means an alkanoyl group having 1 to 7 carbon atoms, a cycloalkylcarbonyl group having a total of 4 to 8 carbon atoms, a cycloalkylalkanoyl group having a total of 5 to 10 carbon atoms, or an arylcarbonyl, aralkanoyl or phenyl sulphonyl group optionally substituted by a fluorine, chlorine, or bromine atom or an alkyl or alkoxy group, the aryl group means a phenyl group optionally substituted by a fluorine, chlorine or bromine atom, by a hydroxy, alkyl, alkoxy, phenylalkoxy or trifluoromethyl group, wherein the alkyl moiety may contain 1 to 4 carbon atoms in each case, or a naphthyl group, the cycloalkyl group means a cycloalkyl group having 3 to 7 carbon atoms, which may be substituted by one or two alkyl groups, and the remaining alkyl and alkanoyl groups mentioned in the 295 definition of the radicals R x to R 6 mean in each case alkyl or alkanoyl groups having 1 to 3 carbon atoms, mixtures of the l- and 3-isomers thereof and the salts thereof with inorganic or organic acids or bases.
2. Benzimidazoles of the formula I according to claim 1, in which R x to R 3 , R 5 and R 6 are as defined in claim 1, and R 4 is a carboxy, aminoacetylamino, trifluoromethylcarbonylamino, trifluoromethylcarbonyl aminomethyl, trifluoromethylsulphonylamino, trifluoromethylsulphonylaminomethyl or 1H-tetrazolyl group, an alkylcarbonylamino, alkylcarbonylaminomethyl, arylcarbonylamino, arylcarbonylaminomethyl, aralkyl carbonyl amino, aralkylcarbonylaminomethyl, alkylsulphonylamino, alkylsulphonylaminomethyl, aryl sulphonylamino; arylsulphonylaminomethyl, aralkyl sulphonyl amino, aralkylsulphonylaminomethyl, aryl sulphonylaminocarbonyl or benzyl sulphonylaminocarbonyl group, an alkyl sulphonylaminocarbonyl or perfluoroalkylsulphonylaminocarbonyl group each having 1 to 6 carbon atoms in the alkyl moiety, an alkoxycarbonyl group having a total of 2 to 7 carbon atoms, an aralkoxycarbonyl group, a pivaloyl oxymethoxycarbonyl, phthalidylmethoxycarbonyl, ethoxycarbonyloxyethoxycarbonyl, methoxymethoxycarbonyl, cyclohexyloxycarbonylmethoxycarbonyl or (1,3-dioxa-2oxo- 4 -methyl - cyclopenten-5 -yl) -methoxycarbonyl group, mixtures of the 1- and 3-isomers thereof and the salts thereof with inorganic or organic acids or bases.
3. Benzimidazoles of the formula I according to claim 1, in which R x denotes a hydrogen, fluorine or chlorine atom, a trifluoromethyl, hydroxy, benzyloxy, carboxy, cyano, amino, nitro, aminosulphonyl, methylaminosulphonyl. 296 dimethylaminosulphonyl, trifluoromethylsulphonyloxy or tetrazolyl group, an alkyl group having 1 to 4 carbon atoms, wherein the methyl group may be additionally substituted by a hydroxy or alkylamino group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, which may be substituted in the 2, 3 or 4 position by a hydroxy, alkoxy, alkylamino, dialkylamino or imidazolyl group and the alkyl substituent may contain 1 to 3 carbon atoms in each case, an alkanoyloxy group having 1 to 4 carbon atoms or a cycloalkylaminocarbonyloxy group having 5 to 7 carbon atoms in the cycloalkyl moiety, an amino group, which is substituted by a benzyl, decal in, trifluoromethylcarbonyl, benzyl carbonyl, benzyloxycarbonyl, 2-ethyl-5-methyl-cyclohexyloxy or tert.butoxycarbonylaminoacetyl group, by an alkyl group having 1 to 5 carbon atoms, by a cycloalkyl, cycloalkylalkyl, cycloalkoxycarbonyl, cycloalkyl carbonyl or cycloaikylalkanoyl group, wherein the cycloalkyl moiety may contain 5 to 7 carbon atoms, the alkyl moiety may contain 1 to 3 carbon atoms and the alkanoyl moiety may contain 1 to 3 carbon atoms, by an alkanoyl group having 1 to 6 carbon atoms, by an aminoalkanoyl or dialkylaminoalkanoyl group, in which the alkyl moiety and the alkanoyl moiety may each contain 1 to 3 carbon atoms, by an alkoxycarbonyl group having a total of 2 to 7 carbon atoms, by an alkyl sulphonyl group having 1 to 4 carbon atoms or by a thiazolidin-3-ylcarbonyl group substituted by an alkoxycarbonyl group having a total of 2 to 4 carbon atoms, a benzylamino or alkylamino group having 1 to 5 carbon atoms, which is substituted at the nitrogen atom 297 additionally by a benzyl or cyclohexyl group, by an alkyl group having 1 to 3 carbon atoms, which may be substituted in the 2 or 3 position by an alkoxy group having 1 to 3 carbon atoms or by a phenylamino group, by 5 an alkanoyl group having 1 to 5 carbon atoms, which may be substituted by an alkoxy group having 1 to 3 carbon atoms, by a cycloalkyl carbonyl group having a total of 6 to 8 carbon atoms or by an alkoxycarbonyl group having a total of 2 to 4 carbon atoms, a carbonyl group which is substituted by an alkyl group which may be substituted in the 2 or 3 position by a hydroxy, alkoxycarbonyl or alkylamino group, by an alkylamino group having 1 to 5 carbon atoms which may be 15 substituted in the alkyl moiety by a carboxy group, by an alkylamino group which is substituted in the 2 or 3 position by a phenylamino group, by a phenyl, alkoxy, amino, benzylamino, phenyl ethyl amino, cycloalkylamino, or cycloalkylalkyiamino group, wherein the alkyl moiety 20 may contain 1 to-3 carbon atoms and the cycloalkyl moiety may contain 5 to 7 carbon atoms, in each case, and additionally an alkylamino group having 1 to 5 carbon atoms may be substituted at the nitrogen atom by an alkyl group having 1 to 4 carbon atoms, an aminocarbonylamino or aminothiocarbonylamino group, which may be monosubstituted, disubstituted or trisubstituted by an alkyl group having 1 to 12 carbon atoms, by an alkenyl or alkynyl group having 3 to 5 30 carbon atoms in each case, by a bicyclic or tricyclic alkyl group having 7 to 11 carbon atoms, by a cycloalkyl, cycloalkylalkyl or phenylalkyl group, wherein the substituents may be the same or different, and the alkyl moiety may contain 1 to 3 carbon atoms and 35 the cycloalkyl moiety may contain 5 to 7 carbon atoms, and a methylene group in a cycloalkyl radical having 5 to 7 carbon atoms may be replaced by an oxygen atom, and an alkyl group may be substituted in the 4, 5 or 6 298 position by a hydroxy or trifluoroacetyl group, a cycloalkyleneiminocarbonylamino group having 4 to 6 carbon atoms in the cycloalkyleneimino moiety or a morphol inocarbonylamino group, which may both be substituted at the amino nitrogen by an alkyl group having 1 to 12 carbon atoms, by a cycloalkyl, cycloalkylalkyl or phenylalkyl group, in which the alkyl moiety may contain l to 3 carbon atoms and the cycloalkyl moiety may contain 5 to 7 carbon atoms, a phthalimino, homophthal imino, 2-carboxyphenyl carbonyl amino, 2-carboxyphenylmethylamino, 2carboxyphenylmethylenecarbonylamino, or 2-carboxycarboxyme thy lenephenyl carbonyl amino group, wherein a carbonyl group in a phthalimino group may be replaced by a methylene group, and a methylene group in a homopthalimino, 2-carboxyphenylmethylenecarbonyl amino or 2 - carboxymethylenephenyl carbonylamino group may be substituted by one or two methyl groups, and additionally the above phenyl nuclei may be mono or disubstituted by methyl or methoxy groups, whilst the substituents may be the same or different, and may at the same time be completely or partially hydrogenated, a bicycloalkane-3-carboxylic acid amino or bicycloalkane3-carboxylic acid amino group, a bicycloalkane-2,3dicarboxylic acid imino or bicycloalkane-2,3,dicarboxylic acid imino group substituted in the 2 position by a carboxy group, wherein the bicycloalkane and bicycloalkene moiety each contain 9 or 10 carbon atoms, may be substituted by 1, 2 or 3 methyl groups and an endomethylene group may be replaced by an oxygen atom, a glutaric acid imino or 3-carboxy-npropylenecarbonyl group, in which the n-propylene group may be perfluorinated in each case, may be substituted by one or two alkyl groups or by a tetramethylene or pentamethylene group, or J 299 a 5,7-dioxa-ΙΗ, 3H-imidazo[1, 5-c] thiazolyl group, a 2imidazolidon-l-yl group optionally substituted in the 3 position by an alkyl group having 1 to 3 carbon atoms, or a 3,4,5,6-tetrahydro-2-pyrimidon-l-yl group, R 2 denotes a hydrogen, fluorine or chlorine atom, a methyl, hydroxy or methoxy group, or R x and R 2 together with the two ortho position carbon atoms of the neighbouring phenyl ring denote a phenyl or 1-alkyl-3,3-dialkyl-2,3-dihydropyrrol-2-one group, in which the alkyl moiety may contain 1 to 3 carbon atoms in each case, R 3 denotes a hydrogen, fluorine or chlorine atom, a hydroxy, benzyl or aminocarbonyl group, an alkyl group having 1 to 5 carbon atoms, wherein the methyl group may be additionally substituted by a hydroxy group, by an alkoxy, alkylsulphenyl, alkylsulphinyl or alkylsulphonyl group each having 1 to 3 carbon atoms, a cycloalkyl or cycloalkylalkyl group, in which the cycloalkyl moiety may contain 5 to 7 carbon atoms and the alkyl moiety may contain 1 to 3 carbon atoms, an alkenyl or alkynyl group each having 3 to 5 carbon atoms, a phenylalkyl group having 1 to 3 carbon atoms, an alkylamino group having 1 to 4 carbon atoms, a pyridyl, furyl, thiazolyl or pyrazolyl group, which may be substituted by one or two methyl groups, R4 denotes an alkoxycarbonyl having a total of 1 to 5 carbon atoms, an amino, phthal imino, aminomethyl, carboxy, cyano, methylsulphonylaminocarbonyl, trif luoromethylsulphonylaminocarbonyl, benzene sulphonyl300 aminocarbonyl, trifluoro-methylcarbonylaminomethyl, trifluoro-methylaminomethyl, tetrazolyl or 1(triphenylmethyl)-tetrazolyl group, R 5 and R 6 denote a hydrogen atom or R s and R 6 together with the two ortho position carbon atoms denote a phenyl group, mixtures of the 1- and 3isomers thereof and addition salts thereof with inorganic or organic acids or bases.
4. Benzimidazoles of the formula I according to claim 1, in which R x denotes an amino group, which is substituted by a benzyl, Decalin, trifluoromethylcarbonyl, benzylcarbonyl , benzyloxycarbonyl, 2-ethyl-5-methylcyclohexyloxy or tert.butoxycarbonylaminoacetyl group, by an alkyl group having 1 to 5 carbon atoms, by a cycloalkyl, cycloalkylalkyl, cycloalkoxycarbonyl, cycloalkylcarbonyl or cycloalkylalkanoyl group, wherein the cycloalkyl moiety may contain 5 to 7 carbon atoms, the alkyl moiety may contain 1 to 3 carbon atoms and the alkanoyl moiety may contain 1 to 3 carbon atoms, by an alkanoyl group having i to 6 carbon atoms, by an aminoalkanoyl or dialkylaminoalkanoyl group, in which the alkyl moiety and the alkanoyl moiety may each contain 1 to 3 carbon atoms, by an alkoxycarbonyl group having a total of 2 to 7 carbon atoms, by an alkyl sulphonyl group having 1 to 4 carbon atoms or by a thiazolidin-3-ylcarbonyl group substituted by an alkoxycarbonyl group having a total of 2 to 4 carbon atoms, a benzyl amino or alkylamino group having 1 to 5 carbon atoms, which is additionally substituted at the nitrogen atom by a benzyl or cyclohexyl group, by an alkyl group having 1 to 3 carbon atoms, which may be substituted in 301 the 2 or 3 position by an alkoxy group having 1 to 3 carbon atoms or by a phenylamino group, by an alkanoyl group having 1 to 5 carbon atoms, which may be substituted by an alkoxy group having 1 to 3 carbon 5. Atoms, by a cycloalkylcarbonyl group having a total of 6 to 8 carbon atoms or by an alkoxycarbonyl group having a total of 2 to 4 carbon atoms, an aminocarbonylamino or aminothiocarbonylamino group, Τθ which may be monosubstituted, disubstituted or trisubstituted by an alkyl group having 1 to 12 carbon atoms, by an alkenyl or alkynyl group each having 3 to 5 carbon atoms, by a bicyclic or tricyclic alkyl group having 7 to 11 carbon atoms, by a cycloalkyl, cycloalkylalkyl or phenylalkyl group, wherein the substituents may be the same or different, and the alkyl moiety may contain 1 to 3 carbon atoms and the cycloalkyl moiety may contain 5 to 7 carbon atoms, and a methylene group in a cycloalkyl radical having 5 to 7 carbon atoms may be replaced by an oxygen atom, and an alkyl group may be substituted in the 4, 5 or 6 position by a hydroxy or trifluoroacetyl group, a cycloalkyleneiminocarbonylamino group having 4 to 6 carbon atoms in the cycloalkyleneimino moiety or a morpholinocarbonylamino group, which may both be substituted at the amino nitrogen by an alkyl group having 1 to 12 carbon atoms, by a cycloalkyl, cycloalkylalkyl or phenylalkyl group, in which the alkyl moiety may contain 1 to 3 carbon atoms and the cycloalkyl moiety may contain 5 to 7 carbon atoms, a phthalimino, homophthal imino, 2-carboxyphenyl carbonyl amino, 2-carboxyphenylmethylamino, 2carboxyphenylmethylenecarbonylamino, or 2-carboxycarboxymethylenephenylcarbonyl amino group, wherein a carbonyl group in a phthalimino group may be replaced by a methylene group, and a methylene group in a 302 homopthal imino, 2 - carboxypheny lmethy 1 enecarbonyl amino or 2-carboxymethylenephenylcarbonylamino group may be substituted by one or two methyl groups, and additionally the above phenyl nuclei may be mono or disubstituted by methyl or methoxy groups, whilst the substituents may be the same or different, and may at the same time be completely or partially hydrogenated, a bicycloalkane-3-carboxylic acid amino or bicycloalkane3-carboxylic acid amino group, a bicycloalkane-2,3dicarboxylic acid imino or bicycloalkane-2,3,dicarboxylic acid imino group substituted in the 2 position by a carboxy group, wherein the bicycloalkane and bicycloalkene moiety each contain 9 or 10 carbon atoms, may be substituted by 1, 2 or 3 methyl groups and an endomethylene group may be replaced by an oxygen atom, a glutaric acid imino or 3-carboxy-npropylenecarbonyl group, in which the n-propylene group may be perfluorinated in each case, may be substituted by one or two alkyl groups or by a tetramethylene or pentamethylene group, or a 5,7-dioxa-lH,3H-imidazo[1,5-c]thiazolyl group, R 2 denotes a hydrogen atom, a methyl or hydroxy group, or R x and R 2 together with the two ortho position carbon atoms of the neighbouring phehyl ring denote a phenyl group, R 3 denotes an alkyl group having 3 to 5 carbon atoms, an alkenyl or alkynyl group each having 3 to 5 carbon atoms, R4 denotes a carboxy, methylsulphonylaminocarbonyl, trifluoromethyl sulphonylaminocarbonyl, benzenesulphonyl aminocarbonyl, trifluorocarbonylaminomethyl, trifluoromethylaminomethyl or tetrazolyl group, 303 R 5 and R 6 each denote a hydrogen atom or R s and Rg together with the two ortho position carbon atoms denote a phenyl group, mixtures of the 1- and 35 isomers thereof and addition salts thereof with inorganic or organic acids or bases.
5. Benzimidazoles of the formula I according to claim 1, in which Ri denotes an amino group, which is substituted by an alkanoyl group having 1 to 6 carbon atoms, by an aminoalkanoyl or dialkylaminoalkanoyl group, in which the alkyl moiety and the alkanoyl moiety may each contain 1 to 3 carbon atoms, by an alkoxycarbonyl group having a total of 2 to 7 carbon atoms or by a thiazolidin-3-ylcarbonyl group substituted by an alkoxycarbonyl group having a total of 2 to 4 carbon atoms, a benzylamino or alkylamino group having 1 to 5 carbon atoms, which is substituted at the nitrogen atom by an alkanoyl group having 1 to 5 carbon atoms, which may be substituted by ah alkoxy group having 1 to 3 carbon atoms, by a cycloalkyl carbonyl group having a total of 6 2b to 8 carbon atoms or by an alkoxycarbonyl group having a total of 2 to 4 carbon atoms, an aminocarbonylamino or aminothiocarbonylamino group, which may be monosubstituted, disubstituted or trisubstituted by an alkyl group having 1 to 8 carbon atoms, by an alkenyl or alkynyl group each having 3 to 5 carbon atoms, by a bicyclic or tricyclic alkyl group having 7 to 11 carbon atoms, by a cycloalkyl, cycloalkylalkyl or phenylalkyl group, wherein the 35 substituents may be the same or different, and the alkyl moiety may contain 1 to 3 carbon atoms and the cycloalkyl moiety may contain 5 to 7 carbon atoms, and a 304 methylene group in a cycloalkyl radical having 5 to 7 carbon atoms may be replaced by an oxygen atom, and an alkyl group may be substituted in the 4, 5 or 6 position by a hydroxy or trifluoroacetyl group, a cycloalkyleneiminocarbonylamino group having 4 to 6 carbon atoms in the cycloalkyleneimino moiety or a morpholinocarbonylamino group, which may both be substituted at the amino nitrogen by an alkyl group having l to 8 carbon atoms, by a cycloalkyl, cycloalkylalkyl or phenylalkyl group, in which the alkyl moiety may contain 1 to 3 carbon atoms and the cycloalkyl moiety may contain 5 to 7 carbon atoms, a phthal imino, homophthal imino, 2-carboxyphenyl carbonyl amino, 2-carboxyphenylmethylamino, 2carboxyphenylmethylenecarbonylamino, or 2-carboxycarboxymethylenephenylcarbonyl amino group, wherein a carbonyl group in a phthal imino group may be replaced by a methylene group, and a methylene group in a homopthalimino, 2-carboxypheny lmethylenecarbonyl amino or 2-carboxymethylenephenylcarbonylamino group may be substituted by one or two methyl groups, and additionally the above phenyl nuclei may be mono or disubstituted by methyl or methoxy groups, whilst the substituents may be the same or different, and may at the same time be completely or partially hydrogenated, a bicycloalkane-3-carboxylic acid amino or bicycloalkane3-carboxylic acid amino group, a bicycloalkane-2,3dicarboxylic acid imino or bicycloalkane-2,3,dicarboxylic acid imino group substituted in the 2 position by a carboxy group, wherein the bicycloalkane and bicycloalkene moiety each contain 9 or 10 carbon atoms, may be substituted by 1, 2 or 3 methyl groups, and an endometbylene group may be replaced by an oxygen atom, a glutaric acid imino or 3-carboxy-npropylenecarbonyl group, in which the n-propylene group may be perfluorinated in each case, may be substituted 305 by one or two alkyl groups or by a tetramethylene or pentamethylene group, or a 5,7-dioxa-lH,3H-imidazo[1,5-c]thiazolyl group, R 2 denotes a hydrogen atom, R x and R 2 together with the two ortho position carbon atoms of the neighbouring phenyl ring denote a phenyl 1Q group, R 3 denotes an alkyl group having 3 to 5 carbon atoms, an alkenyl or alkynyl group each having 3 to 5 carbon atoms, R 4 denotes a carboxy or tetrazolyl group, R 5 and R e denote a hydrogen atom or 20 R5 and R 6 together with the two ortho position carbon atoms denote a phenyl group, mixtures of the 1- and 3isomers thereof and addition salts thereof with inorganic or organic acids or bases.
6. Benzimidazoles of the formula I according to claim 1: Z5 4' - [ (2-n-butyl-6- (N- (n-hexylaminocarbonyl) -benzylamino)benz imidazol -1-yl) -methyl ] biphenyl - 2 - carboxylic acid, 4 1 -[(2-n-butyl-6-(N-cyclohexylaminocarbonyl-nbutylamino)-benzimidazol-l-yl)-methyl]biphenyl-2carboxylic acid, 4 1 -[(2-n-butyl-6-(N-cyclohexylaminocarbonyl-ethylamino)benzimidazol-l-yl) -methyl]biphenyl-2-carboxylic acid, 4' - [ (2-n-butyl-6- (N-cyclohexylaminocarbonyl-npropylamino) -benzimidazol-l-yl) -methyl] biphenyl-2306 carboxylic acid, 4'-[(2-n-butyl-6-(N-cyclohexylaminocarbonylmethylamino) -benzimidazol-l-yl) -methyl]biphenyl-2carboxylic acid, 4' - [ (2-n-butyl-6-cyclohexylaminocarbonylaminobenzimidazol-l-yl) -methyl]biphenyl-2-carboxylic acid, 4' - [ (2-n-butyl-6 - (N-cyclohexylaminocarbonyl-npentylamino) -benzimidazol-l-yl) -methyl]biphenyl-2carboxylic acid, 4’ - [ (2-n-butyl-6- (N-methylaminocarbonyl-benzylamino) benzimidazol-l-yl) -methyl] biphenyl-2-carboxylic acid, 4' - [ (2-n-butyl-6- (l-oxo-isoindolin-2-yl) -benzimidazol-lyl)-methyl] biphenyl-2-carboxylic acid, 4' - [ (2-n-butyl-67 (N-eye lohexyl aminocarbonyl benzylamino) -benzimidazol-l-yl) -methyl] biphenyl-2carboxylic acid, 4 ' - [ (2-n-butyl-6-n-pentanoylamino-benzimidazol-l-yl) methyl] biphenyl-2-carboxylic acid, 4 1 - [ (2 -n-butyl - 6 -propionylamino-benzimidazol - 1-yl )methyl]biphenyl-2-carboxylic acid, 4' - [ (2-n-bu.tyl-6-isopropylcarbonylamino-benzimidazol-lyl)-methyl]biphenyl-2-carboxylic acid, 4 1 -[(2-n-butyl-6-(tetrahydropyran-2-ylaminocarbonylamino) -benzimidazol-l-yl) -methyl] biphenyl2-carboxylic acid, 4' -[(2-n-butyl-6-(n-butylaminocarbonylamino)benz imidazol -1-yl) -methyl ] biphenyl - 2 - carboxyl ic acid, 307 4'-[(6-n-butanoylamino-2-n-butyl-benzimidazol-l-yl)methyl]biphenyl-2-carboxylic acid, 4'-[(2-n-butyl-6-(N-ethoxycarbonyl-benzylamino)benzimidazol-l-yl) -methyl]biphenyl-2-carboxylic acid, 4 ’ - [ (2-n-butyl-6 - (N- (dimethylaminocarbonyl) -amino) benzimidazol-l-yl) -methyl]biphenyl-2-carboxylic acid, 4 · — [ (2-n-butyl-6- (N-cyclohexylaminocarbonyl-nhexylamino) -benzimidazol-l-yl) -methyl] biphenyl-2carboxylic acid, 4 ’ - [ (2-n-butyl-6- ((5-hydroxy-n-pentyl) -aminocarbonylamino) -benzimidazol-l-yl) -methyl] biphenyl-2-carboxylic acid, 4 ’ - [ (2-n-butyl-6- (N-methylaminocarbonyl-n-pentylaraino) benzimidazol-l-yl) -methyl]biphenyl-2-carboxylic acid, 4' - [ (2-n-butyl-6-cyclohexylearbonylamino-benzimidaz0l-lyl)-methyl]biphenyl-2-carboxylic acid, 4 ' - [ (2-n-butyl-6 - (N- (n-butylaminocarhonyl) -methylamino) benzimidazol-l-yl) -methyl]biphenyl-2-carboxylic acid, 4 ’ - [ (2-n-butyl-7-hydroxy-4-methyl-benzimidazol-l-yl) methyl]-2-(lH-tetrazol-5-yl)-biphenyl, 4' - [ (2-n-butyl-6- (cis-hexahydrophthalimino) benz imidazol -1-yl) -methyl ] biphenyl - 2 - carboxylic acid, 4 1 -[(2-n-butyl-6-(N-(dimethylaminocarbonyl)benzylamino) -benzimidazol-l-yl) -methyl]biphenyl-2carboxylic acid, 4'- ((2-n-butyl-6-(N-(n-hexylaminocarbonyl)-N-(2phenylethyl) -amino) -benzimidazol-l-yl) -methyl ] biphenyl 308 2-carboxylic acid and 4' - [ (2-n-butyl-6-cyclopentylcarbonylamino-benzimidazol1-yl)-methyl]biphenyl-2-carboxylic acid, mixtures of the 1- and 3-isomers thereof and addition salts thereof with inorganic or organic acids or bases.
7. Physiologically acceptable addition salts of the compounds according to at least one of claims 1 to 6 with inorganic or organic acids or bases.
8. Medicaments containing a compound according to at least one of claims 1 to 6, in which R 4 is a group containing a Bronsted acid or a radical which may be converted in vivo to a group containing a Bronsted acid, or a physiologically acceptable addition salt thereof in addition to one or more optional inert excipients and/or diluents.
9. Use of a compound according to at least one of claims 1 to 6, in which R 4 is a group containing a Brdnsted acid or a radical which may be converted in vivo to a group containing a Bronsted acid, or a physiologically acceptable addition salt thereof, for the preparation of a medicament which is suitable for the treatment of hypertonia, cardiac insufficiency, ischaemic peripheral circulatory disorders, myocardial ischaemia (Angina), for the prevention of cardiac insufficiency progression after myocardial infarction, for the treatment of diabetic nephropathy, glaucoma, gastrointestinal illnesses and diseases of the bladder.
10. Process for the preparation of a medicament according to claim 8, characterised in that a compound according to at least one of claims 1 to 6 in which R 4 is a group containing a Brdnsted acid or a radical which may be converted in vivo to a group containing a 309 Bronsted acid, or a physiologically acceptable addition salt thereof is incorporated in one or more inert excipients and/or diluents in non-chemical manner.
11. Process for the preparation of the benzimidazoles according to claims 1 to 7, characterised in that a) a compound of the formula in which R x and R 2 are as defined in at least one of claims 1 to 6, one of the radicals X x or Y x is a group of the formula and the other of the radicals X x or Y x is a group of the formula Z. Z_ X / 2 - NH - C - R 3 · wherein R 3 * has the meanings mentioned in at least one of claims 1 to 6 for R 3 , with the exception of the fluorine, 310 chlorine or bromine atom, the hydroxy, mercapto or aminocarbonyl group, wherein the latter may be substituted by an alkyl group having 1 to 3 carbon atoms or by a cycloalkyl group having 5 to 7 carbon atoms, R 4 to Rg are as defined in at least one of claims l to 6, R 7 denotes a hydrogen atom, a hydroxy group or an R 3 ' CO group, wherein R 3 * is defined as mentioned above, Z 3 and Z 2 , which may be the same or different, denote optionally substituted amino groups or hydroxy or mercapto groups optionally substituted by lower alkyl groups, or Z x and Z 2 , together denote an oxygen atom or sulphur atom, an imino group optionally substituted by an alkyl group having 1 to 3 carbon atoms, an alkylenedioxy or alkylenedithio group each having 2 or 3 carbon atoms, but wherein one of the radicals Χ 3 or Y T must be a group of the formula or . NH Z 1 /2 - Ris cyclised, or b) for the preparation of the compounds of the formula I, in which R 3 represents the aromatic or heteroaromatic radicals mentioned in at least one of claims 1 to 6 for 311 R 3 , a phenylenediamine of the formula in which R x and R 2 are as defined in at least one of claims 1 to 6, one of the radicals X 2 or Y 2 denotes a group of the formula in which R 4 to R 6 are as defined in at least one of claims 1 to 6/ and the other of the radicals X 2 or Y 2 denotes an amino group, is reacted with an aldehyde of the formula OCH -R 3 (IV) in which R 3 denotes the aromatic or heteroaromatic radicals mentioned in at least one of claims 1 to 6 for R 3 , in the presence of an oxidising agent, or 312 c) for the preparation of compounds of the formula I, in which at least one of the radicals R x , R 2 and/or R 3 is one of the radicals containing a sulphinyl or sulphonyl group mentioned in at least one of claims 1 to 6 for R x , R 2 and/or R 3 , and the remainder of the radicals R x , R 2 and/or R 3 are as defined in at least one of claims 1 to 6, a compound of the formula in which R 4 to Rg are as defined in at least one of claims 1 to 6, at least one of the radicals R x ', R 2 * and/or R 3 ' is one of the radicals containing a sulphur atom or a sulphinyl group mentioned in at least one of claims 1 to 6 for R x , R 2 and/or R 3 , and the remainder of the radicals R x ', R 2 ’ and/or R3 1 have the meanings mentioned in at least one of claims 1 to 6 for R x , R 2 and/or R 3 , is oxidised, or d) for the preparation of a compound of the formula I, in which R 4 is a carboxy or amino group, a compound of the formula ,(vi) in which R x to R 3 , R 5 and Rg are as defined in at least one of claims 1 to 6, and 313 R 4 ' is a group which can be converted to a carboxy or amino group, is converted to a corresponding carboxy or amino compound, or e) a benzimidazole of the formula in which R x to R 3 are as defined in at least one of claims 1 to 6, is reacted with a biphenyl compound of the formula .(VIII) in which R4 to R 6 are as defined in at least one of claims 1 to 6, and Z 3 is a nucleophilic leaving group, such as a halogen atom, for example a chlorine, bromine or iodine atom, or a substituted sulphonyloxy group, for example a methanesulphonyloxy, phenylsulphonyloxy or ptoluenesulphonyloxy group, or f) for the preparation of a compound of the formula I, in which R 4 is a 1H-tetrazolyl group, a protective radical is cleaved off from a compound of the formula R- 35 1 · ,CH r - r 6 Il vs— - R \'· / \· ' I ' R 5 . (IX) r 2 —J r~ I v 3 R. ” 314 in which R x to R 3 , R 5 and R 6 are as defined in at least one of claims 1 to 6, and R 4 is a 1H-tetrazolyl group protected in the 1 position by a protective radical, or g) for the preparation of a compound of the formula I, in which R 4 is a 1H-tetrazolyl group, a compound of the formula in which R x to R 3 , R s and Re are as defined in at least one of claims 1 to 6, is reacted with hydrazoic acid, or h) for the preparation of a compound of the formula I, in which R x and/or R 2 is an aminocarbonylamino group, which may be monosubstituted, disubstituted or trisubstituted by a bicyclic or tricyclic alkyl group or by an alkyl, alkenyl, alkynyl, cycloalkyl; cycloalkylalkyl, aralkyl or aryl group, wherein a methylene group in a cycloalkyl radical having 4 to 7 carbon atoms may be replaced by an oxygen atom, a compound of the formula in which 315 R 2 to R 6 are as defined in at least one of claims 1 to 6, and R 8 denotes a hydrogen atom, an alkyl group having l to 20 carbon atoms, an alkenyl or alkynyl group each having 3 to 5 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a cycloalkylalkyl group, in which the cycloalkyl moiety may contain 3 to 7 carbon atoms, the alkyl moiety may contain l to 3 carbon atoms and a methylene group in a cycloalkyl moiety having 4 to 7 carbon atoms may be replaced by an oxygen atom, a bicyclic or tricyclic alkyl group having 7 to 10 carbon atoms, an aryl or aralkyl group having 1 to 3 carbon atoms in the alkyl moiety, wherein the aryl group may be a phenyl group optionally substituted by a fluorine, chlorine or bromine atom, or a hydroxy, alkyl or alkoxy group each having 1 to 4 carbon atoms, is reacted with a compound of the formula CW - z 4 , R 9 , which may be the same or different, have the meanings mentioned above for R 8 , W is an oxygen atom or sulphur atom, Z 4 is a nucleophilic leaving group, such as a chlorine or bromine atom, or also, if at least one of the radicals R 9 is a hydrogen atom, Z 4 and R 9 together are a nitrogen-carbon bond or a cycloalkyleneimino group having 4 to 6 carbon atoms, or a morpholino group, or i) for the preparation of a compound of the formula I, in which R 4 is a trifluoromethylcarbonylamino, trifluoromethylcarbonylaminomethyl, trifluoromethylsulphonylamino, trifluoromethylsulphonylaminomethyl or 1H-tetrazolyl group, an alkylcarbonylamino, alkyl316 carbonylaminomethyl, arylcarbonylamino, arylcarbonylaminomethyl, aralkylcarbonylamino, aralkylcarbonylaminomethyl, alkylsulphonylamino, alkylsulphonylaminomethyl, arylsulphonylamino, arylsulphonylaminomethyl, aralkylsulphonylamino or aralkylsulphonylaminomethyl group, in which the alkyl moiety may contain 1 to 3 carbon atoms in each case, a compound of the formula in which R x to R 3 , R s and R 6 are as defined in at least one of claims 1 to 6, and R 4 ' is an amino or aminomethyl group, is acylated using a compound of the formula HO -Ii -Rio (XIV) (in which R 10 denotes a trifluoromethyi group, an alkyl, aryl or aralkyl group, wherein the alkyl moiety may contain 1 to 3 carbon atoms in each case, and U denotes a carbonyl or sulphonyl group) or using reactive derivatives thereof, such as acid halides, acid esters pr acid anhydrides thereof, or k) for the preparation of a compound of the formula I, in which R 4 is an alkyl sulphonylaminocarbonyl or perfluoroalkylsulphonylamino group each having 1 to 4 carbon atoms in the alkyl moiety, or is a benzylsulphonylaminocarbonyl group, a reactive derivative of a carboxylic acid of the formula 317 ,(XV) in which R x to R 3 , R 5 and R 6 are as defined in at least one of claims 1 to 6, is reacted with a sulphonamide of the formula H 2 N -SO 2 -Ru (XVI) (in which R lx is an alkyl or perfluoroalkyl group each having 1 to 4 carbon atoms, or is a benzyl group) or with alkali metal salt thereof, or 1) for the preparation of a compound of the formula I, in which R 2 is a 2-imidazolidon-l-yl or 3,4,5,6tetrahydr0-2-pyrimidon-l-yl group optionally substituted in the 3 position by an alkyl, cycloalkyl, cycloalkylalkyl or aralkyl group, a compound of the formula in which R lf R 3 and R 4 to R 6 are as defined in at least one of claims 1 to 6, Hal is a chlorine, bromine or iodine atom, and n is the number 2 or 3, is cyclised and, if required, an NH compound thus obtained is alkylated using a compound of the formula 318 R 12 -Hal (XVIII) in which R 12 is an alkyl, cycloalkyl, cycloalkylalkyl or aralkyl group, and Hal is a chlorine, bromine or iodine atom, or m) for the preparation of compounds of the general formula I, in which R x denotes an amino group, which is monosubstituted by a dialkylaminoalkanoyl, acyl, cycloalkoxycarbonyl, cycloalkylalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl or trifluoroacetyl group, by an alkylsulphonyl group having 1 to 4 carbon atoms, by an alkoxycarbonyl group having a total of 2 to 7 carbon atoms, or by a thiazolidin-3-yl-carbonyl group substituted by an alkoxycarbonyl group, an alkylamino group having 1 to 6 carbon atoms, which may be substituted at the nitrogen atom by an alkylsulphonyl oracyl group, wherein, if the acyl group is an alkanoyl group, it may additionally be substituted by an alkoxy group, and the alkyl substituent may be substituted at position 2 by a hydroxy, alkoxy or arylamino group, an N-alkoxycarbonyl-alkylamino, N-cycloalkoxycarbonylalkylamino, N-cycloalkylalkoxycarbonyl-alkylamino, Naryloxycarbonyl-alkylamino or N-aralkoxycarbonylalkylamino group, in which the alkyl group may contain l to 6 carbon atoms in each case, an alkoxycarbonylamino, cycloalkoxycarbonylamino, cycloalkylalkoxycarbonylamino, aryloxycarbonylamino, aralkoxycarbonylamino, acylamino or alkylsulphonylamino group substituted at the nitrogen atom by a cycloalkyl, cycloalkylalkyl or aralkyl group, or a phthal imino, homophthal imino, 2-carboxyphenylcarbonyl amino, 2-carboxyphenylmethylamino, 2319 carboxyphenylmethylenecarbonylamino, or 2carboxymethylenephenyl carbonyl amino group, wherein a carbonyl group in a phthal imino group may be replaced by a methylene group, and a methylene group in a homopthalimino, 2-carboxyphenylmethylenecarbonyl amino or 2-carboxymethylenephenylcarbonylamino group may be substituted by one or two alkyl groups, and additionally the above phenyl nuclei may be mono or disubstituted by alkyl or alkoxy groups, whilst the substituents may be the same or different, and may at the same time be completely or partially hydrogenated, a bicycloalkane-3carboxylic acid amino or bicycloalkane-3-carboxylic acid amino group, a bicycloalkane-2,3-dicarboxylic acid imino or bicycloalkane-2,3,-dicarboxylic acid imino group substituted in the 2 position by a carboxy group, wherein the bicycloalkane and bicycloalkene moiety each contain 9 or 10 carbon atoms, may be substituted by 1, 2 or 3 methyl groups and an endomethylene group may be replaced by an oxygen atom, a glutaric acid imino or 3carboxy-n-propylenecarbonyl group, in which the npropylene group may be perfluorinated in each case, may be substituted by one or two alkyl groups or by a tetramethylene or pentamethylene group, or and R 4 has the meanings mentioned in at least one of claims 1 to 6 for R 4 , with the exception of the amino group, a compound of the formula in which R 2 , R 3 , R s and Rg are as defined in at least one of claims 1 to 6, R 4 is as defined in at least one of claims 1 to 6, with 320 the exception of the amino group, and R 13 denotes a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, which may be substituted at position 2 by a hydroxy, alkoxy or arylamino group, a cycloalkyl, cycloalkylalkyl or aralkyl group, is acylated using a compound of the formula R 14 -Z 5 (XX) (in which R 14 denotes a dialkylaminoalkanoyl, cycloalkoxycarbonyl, cycloalkylalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl or trifluoroacetyl group, an alkylsulphonyl group having 1 to 4 carbon atoms, an alkoxycarbonyl group having a total of 2 to 7 carbon atoms, a thiazolidin-3-ylcarbonyl group substituted by an alkoxycarbonyl group, or an acyl group, in which, if the acyl group is an alkanoyl group, it may additionally be substituted by an alkoxy group, or a 2carboxypheny1carbonyl, 2-carboxyphenyImet hy 1, 2carboxyphenylmethylenecarbonyl or 2carboxymethylenephenylcarbonyl group, whilst a methylene group in a 2-carboxyphenylmethylenecarbonyl or 2carboxy-methylenephenylcarbonyl group may be substituted by one or two alkenyl groups, and additionally the above phenyl nuclei may be mono or disubstituted by alkyl or alkoxy groups, while the substituents may be the same or different, and may at the same time be completely or partially hydrogenated, a bicycloalkane-3-carbonyl or bicycloalkene-3-carbonyl group substituted in the 2 position by a carboxy group, wherein the bicycloalkane and bicycloalkene moiety each have 9 or 10 carbon atoms, may be substituted by 1, 2 or 3 methyl groups, and an endomethylene group may be replaced by an oxygen atom, a 3-carboxy-n-propylenecarbonyl group, wherein the n-‘ propylene group may be perfluorinated, may be substituted by one or two alkyl groups or by a tetramethylene or pentamethylene group 321 Z 5 denotes a nucleophilic leaving group) or using reactive derivatives thereof, such as acid halides, acid esters or acid anhydrides thereof, and n) for the preparation of compounds of the general Formula I, in which at least one of the groups R x or R 2 is a 2-carboxyphenylcarbonylamino, 2carboxyphenylmethylamino, 2carboxyphenylmethylenecarbonylamino, or 2carboxymethylenephenylcarbonylamino group, whilst a methylene group in a 2carboxyphenylmethylenecarbonylamino or 2carboxymethyleneamino group may be substituted by one or two alkyl groups, and additionally the above phenyl nuclei may be mono or disubstituted by alkyl or alkoxy groups, whilst the substituents may be the same or different, and at the same time may be completely or partially hydrogenated, a bicycloalkane-3-carboxylic acidamino group or bicycloalkene-3-carboxylic acid amino group substituted in the 2 position by a carboxy group, wherein the bicycloalkane and bicycloalkene moiety each contain 9 or 10 carbon atoms, may be substituted by 1, 2 or 3 methyl groups, and an endomethylene group may be replaced by an oxygen atom, a 3-carboxy-npropylenecarbonyl group, wherein the n-propylene group may be perfluorinated, may be substituted by one or two alkyl groups or by a tetramethylene or a pentamethylene group, a compound of the general formula ,(XXI) 35 in which R 2 to R 6 are as defined in at least one of Claims 1 to 6, and R 15 a phthalimino or homophthal imino group, whilst a 322 carbonyl group in a phthalimino group may be replaced by a methylene group and a methylene group in a homophthal imino group may be substituted by one or two alkyl groups, and additionally the above phenyl nuclei may be mono or disubstituted by alkyl or alkoxy groups, whilst the substituents may be the same or different, and at the same time may be completely or partially hydrogenated, a bicycloalkane-2,3-dicarboxylic acid imino or bicycloalkene-2-3-dicarboxylic acid imino group, wherein the bicycloalkane and bicycloalkane moiety each contain 9 or 10 carbon atoms, may be substituted by 1, 2 or 3 methyl groups and an endomethylene group may be replaced by an oxygen atom, a glutaricacidimino group, wherein the n-propylene group may be perfluorinated, may be substituted by one or two alkyl groups or by a tetramethylene or pentamethylene group, is partially hydrolysed, and if required, a protective radical used during the reactions a) to n) to protect reactive groups is cleaved and/or if desired, a compound of the formula I thus obtained, in which R x and/or R 2 is a nitro group, is then converted to a corresponding amino compound of the formula I by means of reduction, or a compound of the formula 1 thus obtained, in which R x and/or R 2 is a hydroxy, amino, alkylamino, phenyl alkyl amino, alkyl sulphonylamino or acylamino group, is converted to a corresponding alkylated compound of the formula I by means of alkylation, or a compound of the formula I thus obtained, in which R x and/or R 2 is a benzyloxy group, is converted to a corresponding compound of the formula I, in which R x and/or R 2 is a hydroxy group, by means of debenzylation, or 323 a compound of the formula I thus obtained, in which R x and/or R 2 is a carboxy group, is converted to a corresponding compound of the formula I, in which R x and/or R 2 is an aminocarbonyl group optionally substituted by one or two alkyl groups each having 1 to 3 carbon atoms, by means of amidation, or a compound of the formula I thus obtained, in which R T and/or R 2 is a carboxy group and/or R 4 is a cyano group, is converted to a corresponding compound of the formula 1θ I, in which R x and/or R 2 is a hydroxymethyl group and/or R 4 is an aminomethyl group, by means of reduction, or a compound of the formula I thus obtained, in which R x and/or R 2 is an alkoxycarbonyl group, is converted to a 15 corresponding compound of the formula I, in which R x and/or R 2 is a carboxy group, by means of hydrolysis, or a compound of the formula I thus obtained, in. which R r and/or R 2 is an alkoxy or phenylalkoxy group, is 20 converted to a corresponding compound of the formula I, in which R x and/or R 2 is a hydroxy group, by means of ether cleaving, or f a compound of the formula I thus obtained, in which R x „ 25 and/or R 2 is an aminocarbonylamino or aminothiocarbonyl group, which is substituted by a cycloalkyl group having 5 to 10 carbon atoms, in which a methylene group is replaced in the 2 position by an oxygen atom, and may be additionally monosubstituted or disubstituted by an 30 alkyl group having 1 to 20 carbon atoms, by an alkenyl or alkynyl group each having 3 to 5 carbon atoms, by a bicyclic or tricyclic alkyl group having 7 to 11 carbon atoms, by a cycloalkyl, cycloalkylalkyl, aralkyl or aryl group, is converted to a corresponding compound of the 35 formula I, in which R x and/or R 2 is an aminocarbonylamino or aminothiocarbonyl group, which is substituted by a 4hydroxy-n-butyl, 5-hydroxy-n-pentyl or 6-hydroxy-n-hexyl 324 group and may additionally be monosubstituted or disubstituted by an alkyl group having 1 to 20 carbon atoms, by an alkenyl or alkynyl group each having 3 to 5 carbon atoms, by a bicyclic or tricyclic alkyl group having 7 to 11 carbon atoms, by a cycloalkyl, cycloalkylalkyl, aralkyl or aryl group, by means of reduction, or a compound of the formula I thus obtained, in which R x and/or R 2 is a phthalimino group, which may be monosubstituted or disubstituted by an alkyl or alkoxy group, wherein the substituents may be the same or different, is converted to a corresponding compound of the formula I, in which R x and/or R 2 is a 1-oxoisoindolin-2-yl group, which may be monosubstituted or disubstituted by an alkyl or alkoxy group, wherein the substituents may be the same or different, by means of reduction, or a mixture of the 1- and 3-isomers of a compound of the formula I thus obtained is separated into its 1-isomer and 3-isomer by means of isomer separation, or a compound of the formula I thus obtained is converted to its addition salt, in particular for the pharmaceutical application to its physiologically acceptable salt with an inorganic or organic acid or base.
12. Process as claimed in claim 11 substantially as described herein with reference to the Examples. 325
13. Benzimidazoles whenever prepared by a method as claimed in any of claims 11 or 12.
14. Process as claimed in claim 10 substantially as described herein 5 with reference to the Examples.
15. A medicament whenever prepared by a process as claimed in claim 10 or claim 14.
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Families Citing this family (95)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2016710A1 (en) * 1989-05-15 1990-11-15 Prasun K. Chakravarty Substituted benzimidazoles as angiotensin ii antagonists
GB8911854D0 (en) * 1989-05-23 1989-07-12 Ici Plc Heterocyclic compounds
IE70593B1 (en) * 1989-09-29 1996-12-11 Eisai Co Ltd Biphenylmethane derivative the use of it and pharmacological compositions containing same
US5250554A (en) * 1989-10-24 1993-10-05 Takeda Chemical Industries, Ltd. Benzimidazole derivatives useful as angiotensin II inhibitors
IL95975A (en) * 1989-10-24 1997-06-10 Takeda Chemical Industries Ltd N-benzyl- 2-alkylbenzimidazole derivatives, their production and pharmaceutical compositions containing them
US5449682A (en) * 1990-02-13 1995-09-12 Merck & Co., Inc. Angiotensin II antagonists incorporating a substituted benzyl element
ES2084801T3 (en) * 1990-02-19 1996-05-16 Ciba Geigy Ag ACIL COMPOUNDS.
DE4006693A1 (en) * 1990-03-01 1991-09-05 Schering Ag NEW BENZIMIDAZOLE DERIVATIVES, METHOD FOR THEIR PRODUCTION AND THEIR PHARMACEUTICAL USE
WO1991016313A1 (en) * 1990-04-13 1991-10-31 Smithkline Beecham Corporation Substituted benzimidazoles
US5196444A (en) * 1990-04-27 1993-03-23 Takeda Chemical Industries, Ltd. 1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate and compositions and methods of pharmaceutical use thereof
US5703110A (en) * 1990-04-27 1997-12-30 Takeda Chemical Industries, Ltd. Benzimidazole derivatives, their production and use
US6004989A (en) 1990-04-27 1999-12-21 Takeda Chemical Industries, Ltd. Benzimidazole derivatives, their production and use
EP0461039B1 (en) * 1990-06-08 1998-09-16 Hoechst Marion Roussel Benzimidazole derivatives, process and intermediates for their preparation, their use as medicaments and pharmaceutical compositions containing them
FR2674523A1 (en) * 1991-03-28 1992-10-02 Roussel Uclaf New benzimidazole derivatives, process for their preparation, the new intermediates obtained, their application as medicaments and the pharmaceutical compositions containing them
AU653524B2 (en) * 1990-06-08 1994-10-06 Roussel-Uclaf New imidazole derivatives, their preparation process, the new intermediates obtained, their use as medicaments and the pharmaceutical compositions containing them
FR2673943B1 (en) * 1991-03-13 1994-02-18 Roussel Uclaf NEW IMIDAZOLE DERIVATIVES, THEIR PREPARATION PROCESS, THE NEW INTERMEDIATES OBTAINED, THEIR APPLICATION AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
FR2670489B1 (en) * 1990-12-18 1994-10-14 Roussel Uclaf NOVEL BENZIMIDAZOLE DERIVATIVES, THEIR PREPARATION PROCESS, THE NEW INTERMEDIATES OBTAINED, THEIR APPLICATION AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
FR2663027B1 (en) * 1990-06-08 1994-12-02 Roussel Uclaf NEW IMIDAZOLE DERIVATIVES, THEIR PREPARATION PROCESS, THE NEW INTERMEDIATES OBTAINED, THEIR APPLICATION AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
WO1991019697A1 (en) * 1990-06-19 1991-12-26 Meiji Seika Kabushiki Kaisha Pyridine derivative with angiotensin ii antagonism
AU636066B2 (en) * 1990-10-30 1993-04-08 Takeda Chemical Industries Ltd. Thienoimidazole derivatives, their production and use
AU657498B2 (en) * 1990-12-14 1995-03-16 Novartis Ag Biphenylyl compounds
DE4224133A1 (en) * 1992-07-22 1994-01-27 Thomae Gmbh Dr K Benzimidazoles, medicaments containing these compounds and process for their preparation
DE4224752A1 (en) * 1992-04-11 1994-02-03 Thomae Gmbh Dr K Benzimidazoles, medicaments containing these compounds and process for their preparation
DE4225756A1 (en) * 1992-01-22 1994-03-10 Thomae Gmbh Dr K Benzimidazoles, medicaments containing these compounds and process for their preparation
SI9210098B (en) * 1991-02-06 2000-06-30 Dr. Karl Thomae Benzimidazoles, drugs with this compounds, and process for their preparation
FR2672891B1 (en) * 1991-02-20 1994-02-18 Synthelabo DERIVATIVES OF 3-PYRAZOLONES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION.
US5616599A (en) * 1991-02-21 1997-04-01 Sankyo Company, Limited Angiotensin II antagosist 1-biphenylmethylimidazole compounds and their therapeutic use
US5236928A (en) * 1991-03-19 1993-08-17 Merck & Co., Inc. Imidazole derivatives bearing acidic functional groups at the 5-position, their compositions and methods of use as angiotensin II antagonists
US5187179A (en) * 1991-03-22 1993-02-16 Merck & Co., Inc. Angiotensin II antagonists incorporating a substituted imidazo [1,2-b][1,2,4]triazole
US5128327A (en) * 1991-03-25 1992-07-07 Merck & Co., Inc. Angiotensin II antagonists incorporating a nitrogen containing six membered ring heterocycle
US5177074A (en) * 1991-03-26 1993-01-05 Merck & Co., Inc. Angiotensin ii antagonists incorporating a substituted thiophene or furan
US5798364A (en) * 1992-03-26 1998-08-25 Merck Patent Gesellschaft Mit Beschrankter Haftung Imidazopyridines
TW274551B (en) * 1991-04-16 1996-04-21 Takeda Pharm Industry Co Ltd
US5252574A (en) * 1991-04-26 1993-10-12 Merck & Co., Inc. Angiotensin II antagonists incorporating a substituted thiophene or furan
US5198438A (en) * 1991-05-07 1993-03-30 Merck & Co., Inc. Angiotensin ii antagonists incorporating a substituted thiophene or furan
US5506361A (en) * 1991-05-08 1996-04-09 Theupjohn Company Imidazobenzoquinones and composition for preventing or treating hypertension or congestive heart failure containing the same
CA2068756A1 (en) * 1991-05-16 1992-11-17 Barry C. Ross Benzofuran derivatives
US5175164A (en) * 1991-06-05 1992-12-29 Merck & Co., Inc. Angiotensin ii antagonists incorporating a substituted indole or dihydroindole
IL102183A (en) * 1991-06-27 1999-11-30 Takeda Chemical Industries Ltd Biphenyl substituted heterocyclic compounds their production and pharmaceutical compositions comprising them
AU644539B2 (en) * 1991-09-10 1993-12-09 Tanabe Seiyaku Co., Ltd. Imidazoindolizine derivatives and process for preparation thereof
TW300219B (en) * 1991-09-14 1997-03-11 Hoechst Ag
EP0543263A3 (en) * 1991-11-16 1993-08-25 Dr. Karl Thomae Gmbh Benziimidazoles, pharmaceuticals containing them and process for their preparation
TW284688B (en) * 1991-11-20 1996-09-01 Takeda Pharm Industry Co Ltd
US5314903A (en) * 1991-12-03 1994-05-24 Neurosearch A/S Benzimidazole compounds useful as calcium channel blockers
DE4219534A1 (en) * 1992-02-19 1993-12-16 Thomae Gmbh Dr K Substituted biphenylyl derivatives, pharmaceutical compositions containing them and methods for their preparation
US5208234A (en) * 1992-03-10 1993-05-04 E. R. Squibb & Sons, Inc. Substituted imidazole phosphonic and phosphinic acid derivatives
GB9218449D0 (en) 1992-08-29 1992-10-14 Boots Co Plc Therapeutic agents
HU219598B (en) * 1992-12-17 2001-05-28 Sankyo Co. Ltd. Imidazole- and pyridine derivatives of biphenyl compounds, process for producing them and pharmaceutical compositions containing them
DK154092D0 (en) * 1992-12-23 1992-12-23 Neurosearch As IMIDAZOLE COMPOUNDS, THEIR PREPARATION AND USE
JP3810020B2 (en) 1993-04-22 2006-08-16 武田薬品工業株式会社 Preventive or therapeutic agent for kidney disease
CZ154994A3 (en) * 1993-07-02 1995-09-13 Senju Pharma Co Visual hypotensive agent
DE4408497A1 (en) * 1994-03-14 1995-09-21 Thomae Gmbh Dr K New bi:phenyl-methyl-benzimidazole derivs.
JPH0853424A (en) 1994-08-11 1996-02-27 Kureha Chem Ind Co Ltd Benzimidazolesulfonic acid amide derivative
JP2001523256A (en) * 1997-05-01 2001-11-20 イーライ・リリー・アンド・カンパニー Antithrombotic substance
TW453999B (en) * 1997-06-27 2001-09-11 Fujisawa Pharmaceutical Co Benzimidazole derivatives
HUP0101439A3 (en) 1998-03-04 2002-09-30 Takeda Chemical Industries Ltd Sustained-release preparation for a ii antagonist, production and use thereof
WO2000078728A1 (en) * 1999-06-22 2000-12-28 Neurosearch A/S Novel benzimidazole derivatives and pharmaceutical compositions comprising these compounds
WO2001057020A1 (en) * 2000-02-01 2001-08-09 Cor Therapeutics, Inc. INDOLE AND BENZIMIDAZOLE INHIBITORS OF FACTOR Xa
JP4730574B2 (en) * 2001-05-18 2011-07-20 山田化学工業株式会社 Benzimidazole compounds, azobenzimidazole compounds and their chelate compounds
EP1444988A4 (en) 2001-11-13 2007-04-25 Takeda Pharmaceutical Anticancer agents
WO2003064414A1 (en) * 2002-01-29 2003-08-07 Vicore Pharma Ab. Tricyclic compounds useful as angiotensin ii agonists
US7232828B2 (en) * 2002-08-10 2007-06-19 Bethesda Pharmaceuticals, Inc. PPAR Ligands that do not cause fluid retention, edema or congestive heart failure
EP1598353A1 (en) * 2004-05-17 2005-11-23 Boehringer Ingelheim International GmbH Pyrrolobenzimidazolones and their use as antiproliferative agents
US7235563B2 (en) 2004-06-21 2007-06-26 Bristol-Myers Squibb Company Spirocyclic compounds useful as modulators of nuclear hormone receptor function
DE102005017605B4 (en) * 2005-04-16 2007-03-15 Sanofi-Aventis Deutschland Gmbh Substituted 2-aminoalkylthio-benzimidazoles, process for their preparation and their use as medicaments
EP1872783B1 (en) * 2005-04-21 2011-12-28 Santen Pharmaceutical Co., Ltd. Therapeutic agent for corneal/conjunctival disorder
TW200838501A (en) * 2007-02-02 2008-10-01 Theravance Inc Dual-acting antihypertensive agents
TWI448284B (en) 2007-04-24 2014-08-11 Theravance Inc Dual-acting antihypertensive agents
CA2688161C (en) 2007-06-04 2020-10-20 Kunwar Shailubhai Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
US8969514B2 (en) 2007-06-04 2015-03-03 Synergy Pharmaceuticals, Inc. Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases
TWI406850B (en) * 2007-06-05 2013-09-01 Theravance Inc Dual-acting benzoimidazole antihypertensive agents
JP2010538071A (en) 2007-09-07 2010-12-09 セラヴァンス， インコーポレーテッド Dual acting antihypertensive
EP2225210B1 (en) 2007-12-11 2012-04-25 Theravance, Inc. Dual-acting benzoimidazole derivative and their use as antihypertensive agents
EP2297113A1 (en) 2008-04-29 2011-03-23 Theravance, Inc. Dual-acting antihypertensive agents
ES2522968T3 (en) 2008-06-04 2014-11-19 Synergy Pharmaceuticals Inc. Guanylate cyclase agonists useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders
ES2624828T3 (en) 2008-07-16 2017-07-17 Synergy Pharmaceuticals Inc. Guanylate cyclase agonists useful for the treatment of gastrointestinal disorders, inflammation, cancer and others
JP2011529072A (en) 2008-07-24 2011-12-01 セラヴァンス， インコーポレーテッド Dual action antihypertensive
WO2011005674A1 (en) 2009-07-07 2011-01-13 Theravance, Inc. Dual-acting pyrazole antihypertensive agents
WO2011011232A1 (en) 2009-07-22 2011-01-27 Theravance, Inc. Dual-acting oxazole antihypertensive agents
EP2470533A4 (en) 2009-08-24 2013-01-23 Ascepion Pharmaceuticals Inc 5,6-bicyclic heteroaryl-containing urea compounds as kinase inhibitors
WO2011090929A1 (en) 2010-01-19 2011-07-28 Theravance, Inc. Dual-acting thiophene, pyrrole, thiazole and furan antihypertensive agents
US9616097B2 (en) 2010-09-15 2017-04-11 Synergy Pharmaceuticals, Inc. Formulations of guanylate cyclase C agonists and methods of use
WO2012170554A1 (en) 2011-06-06 2012-12-13 Theodore Mark Kamenecka N-biphenylmethylindole modulators of pparg
WO2012170561A1 (en) 2011-06-06 2012-12-13 The Scripps Research Institute (T.S.R.I.) N-benzylindole modulators of pparg
WO2013078233A1 (en) * 2011-11-22 2013-05-30 Ripka Amy S N-benzylbenzimidazole modulators of pparg
WO2013078240A1 (en) 2011-11-22 2013-05-30 Ripka Amy S N-biphenylmethylbenzimidazole modulators of pparg
AU2013221475B2 (en) 2012-02-17 2016-10-20 Kineta Four Llc Antiviral drugs for treatment of Arenavirus infection
EP2970384A1 (en) 2013-03-15 2016-01-20 Synergy Pharmaceuticals Inc. Agonists of guanylate cyclase and their uses
US9486494B2 (en) 2013-03-15 2016-11-08 Synergy Pharmaceuticals, Inc. Compositions useful for the treatment of gastrointestinal disorders
WO2014165815A2 (en) * 2013-04-04 2014-10-09 University Of Maryland, Baltimore Nonsteroidal and steroidal compounds with potent androgen receptor down-regulation and anti prostate cancer activity
JP6606491B2 (en) 2013-06-05 2019-11-13 シナジー ファーマシューティカルズ インコーポレイテッド Ultra high purity agonist of guanylate cyclase C, method for producing and using the same
US10016394B2 (en) 2014-04-16 2018-07-10 The Scripps Research Institute PPARG modulators for treatment of osteoporosis
EP3383388B1 (en) 2015-11-30 2021-04-14 Merck Sharp & Dohme Corp. Aryl acylsulfonamides as blt1 antagonists
CN110105338A (en) * 2019-05-31 2019-08-09 东华大学 6 '-replace amine formyl benzimidazole -4- substituent methyl indole derivatives
CN110669012A (en) * 2019-11-28 2020-01-10 陈志龙 Fluorine-substituted benzimidazole derivative, preparation method thereof and application in medical field

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE142754C (en) *
DE253310C (en) *
DE132606C (en) *
DE291969C (en) * 1913-02-13
US4612323A (en) * 1983-06-27 1986-09-16 Sumitomo Chemical Company, Limited Insecticidal and acaricidal derivatives of 1-benzylbenzimidazole
EP0142754A2 (en) * 1983-11-04 1985-05-29 Ferrer Internacional, S.A. 2-Substituted-benzoic acid imidazoles, process for preparing them and pharmaceutical compositions containing them
CA1334092C (en) * 1986-07-11 1995-01-24 David John Carini Angiotensin ii receptor blocking imidazoles
US4820843A (en) * 1987-05-22 1989-04-11 E. I. Du Pont De Nemours And Company Tetrazole intermediates to antihypertensive compounds
US4880804A (en) * 1988-01-07 1989-11-14 E. I. Du Pont De Nemours And Company Angiotensin II receptor blocking benzimidazoles
IL95975A (en) * 1989-10-24 1997-06-10 Takeda Chemical Industries Ltd N-benzyl- 2-alkylbenzimidazole derivatives, their production and pharmaceutical compositions containing them

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